CN115850115A - Ruxolitinib intermediate and preparation method thereof - Google Patents
Ruxolitinib intermediate and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a ruxolitinib intermediate and a preparation method thereof. The invention provides a compound shown as a formula VI, a compound shown as a formula V or a diastereoisomer mixture of the compounds and a preparation method thereof. The compound I with the ee value of more than 98 percent is efficiently prepared by the preparation method and the corresponding intermediate; the related preparation method has high yield, andthe intermediate is stable, and the compound can be recycled and repeatedly split, so that the optimization of material utilization is achieved.
Description
Technical Field
The invention relates to a ruxolitinib intermediate and a preparation method thereof.
Background
The united states FDA officially approved ruxolitinib (trade name Jakafi) in 2011 as the first drug for the treatment of Myelofibrosis (MF) and qualified for rare medications. Is suitable for treating moderate or high risk MF including primary MF, MF after polycythemia vera and MF after primary thrombocythemia.
The concrete structure is as follows:
at present, the synthesis of ruxolitinib raw material medicines is reported in literatures. The following schemes are mainly provided:
the method comprises the following steps: in the patent W02010083283, SM1 and SM2 are butted through a Suzuki reaction to obtain an intermediate A, conjugated addition is carried out on alkenyl nitrile-NH-under an alkaline condition to obtain an intermediate B, the intermediate B is separated through chiral column chromatography to obtain an intermediate C, and then an SEM protecting group is removed to obtain ruxolitinib. The disadvantages of the route are: the chiral column chromatographic separation has high cost and is not suitable for industrial production.
The second method comprises the following steps: the patent W02010083283 also reports that the intermediate B is separated by a resolution means, and the used resolving agent is D- (+) -dibenzoyltartaric acid. The disadvantages of the route are: the resolution reagent is relatively uncommon and high in price; and the ee value is not high after one-time resolution, and the API (ruxolitinib bulk drug) with high chiral purity can be obtained through multiple resolution methods. Therefore, the API produced by this resolution method is quite expensive and has no competitive advantage.
The third method comprises the following steps: IN patent IN202021005413, roxolitinib is obtained by reducing the chirality of E to F, obtaining G by MsCl, and performing nucleophilic substitution reaction on G and H to obtain I, I and G through coupling. The disadvantage of this patent is that the chiral purity of F by reduction of E with R-CBS is not disclosed and, according to our actual replicates, the ee of F is optimally 60% and far from meeting the requirements of acceptable (99% chemical purity, 98% ee) ruxolitinib.
The method comprises the following steps: patent CN107674026A discloses that compound II is subjected to chiral reduction by R-CBS to prepare compound III, and then subsequent reaction is carried out, wherein the ee value of compound III is not less than 98%. We have repeated all the examples in this patent, with the result that the ee value of compound III does not exceed 63% at the most.
The choice of configuration is crucial for the synthesis of ruxolitinib. The key step of configuration selection in the first method and the second method is that the intermediate B is separated or resolved by a chromatographic column to obtain an intermediate C with a corresponding configuration. The key step of configuration selection in the third and fourth methods is the reduction of 3-oxo-3-cyclopentylpropanenitrile by a chiral borane reagent, R-CBS, to stereoselectively select (S) -3-cyclopentyl-3-hydroxypropionitrile. After selective reduction, the ee value is low, and the description of the requirement cannot be met; and the product is oily, the obtained crude product is a mixture of the product and isomers thereof, and the chiral purity cannot be improved by a conventional purification mode.
In summary, it is necessary to synthesize a chiral intermediate with an effective, key and high ee value for preparing ruxolitinib by a certain synthesis method, so as to improve the production efficiency of ruxolitinib, reduce the production cost, and facilitate industrial production.
Disclosure of Invention
The invention provides a ruxolitinib intermediate and a preparation method thereof. The invention aims to provide a method for efficiently obtaining a ruxolitinib intermediate with high chiral purity and a corresponding intermediate, and the method efficiently prepares (S) -3-cyclopentyl-3-hydroxypropionitrile with an ee value of up to 98% through mild conditions and the corresponding intermediate; the related preparation method has high yield, stable corresponding intermediate, and repeated resolution of the compound, and can realize the optimization of material utilization.
The invention provides a compound shown as a formula VI, a compound shown as a formula V or a diastereoisomer mixture of the compounds shown as the formula VI and the formula V:
the invention also provides a preparation method of the compound shown in the formula VI or the compound shown in the formula V, which comprises the following steps:
in a solvent, carrying out condensation reaction on a compound shown as a formula IV and a resolving agent shown as a formula A to obtain a compound shown as a formula VI or a compound shown as a formula V;
the compound shown in the formula IV is a mixture of a compound shown in a formula IV 'and a compound shown in a formula IV';
in the preparation method, the molar ratio of the resolving agent A to the compound shown in the formula IV can be determined by referring to the conventional amount in chiral resolution in the field, and preferably (0.9-1.5): 1, such as 1.2.
In the preparation method, the solvent can be a conventional solvent for condensation reaction in the field, preferably an aprotic solvent, and more preferably dichloromethane.
In the preparation method, the mass ratio of the solvent to the compound shown in the formula IV can be referred to the conventional dosage of chiral resolution in the field, and preferably (1-20): 1, such as 5:1.
In the preparation method, the condensation reaction can also be carried out in the presence of a condensation reagent or in the absence of the condensation reagent.
When the condensation reaction is carried out in the presence of a condensing agent,
the molar ratio of the condensation reagent to the compound of formula IV may be that conventionally used in the art for condensation reactions, and is preferably (0.9-1.5): 1, e.g. 1.2.
The condensation reagent may be a condensation reagent conventional in the art for condensation reactions, preferably DCC, CDI, EDCI, HATU or HBTU, e.g. EDCI.
In the preparation method, the condensation reaction can be carried out in the presence of a catalyst or in the absence of a catalyst.
When the condensation reaction is carried out in the presence of a catalyst,
the molar ratio of the catalyst to the compound of formula IV may be the amount conventionally used in condensation reactions in the art, and is preferably (0.1-1.5): 1, preferably 1.2.
The catalyst may be a conventional catalyst for condensation reactions in the art, preferably HOBt or DMAP, for example DMAP.
In the preparation method, the condensation reaction can be carried out in a protective gas atmosphere, and the protective gas is preferably nitrogen.
In the preparation method, the reaction time of the condensation reaction can be 1-24h, and preferably 2h.
The condensation reaction may also include a post-treatment after the end of the condensation reaction.
The post-treatment can also comprise recrystallization, and the product obtained after the condensation reaction is finished is recrystallized in a solvent to obtain a recrystallized solid and a recrystallized mother liquor (wherein the recrystallized solid is a compound shown as a formula VI, and the recrystallized mother liquor contains a compound shown as a formula V).
In the recrystallization, the solubility difference of the solvent to the compound shown in the formula VI and the compound shown in the formula V is large, so that the separation is facilitated; the invention is preferably an ester solvent, a halogenated hydrocarbon solvent, an alcohol solvent, a ketone solvent, a nitrile solvent or an ether solvent; further preferred is ethyl acetate, dichloromethane, methanol, ethanol, acetone, acetonitrile or methyl tert-butyl ether, for example methyl tert-butyl ether or dichloromethane.
In the recrystallization, the mass ratio of the product obtained after the condensation reaction to the solvent is preferably 1: (2-10), for example 1:6.
In the post-treatment, the method may further comprise the following steps before the recrystallization:
(c) Quenching the reaction solution after the condensation reaction with water, and separating an organic phase;
(d) Washing the organic phase separated in the step (c) by dilute hydrochloric acid, a sodium carbonate solution and a salt solution in sequence; the concentration of the dilute hydrochloric acid is 0.5mol/L, the mass concentration of the sodium carbonate solution is 5%, and the mass concentration of the salt solution is 20%;
the mass concentration is the mass percentage of the solute in the solution;
(e) And (d) drying and concentrating the organic phase washed in the step (d) to obtain a crude product of the compound shown in the formula VI or the compound shown in the formula V.
In the production method, the condensation reaction may occur in the presence of the condensation agent and the catalyst.
The preparation method preferably comprises the following steps:
(a) In the solvent, mixing the resolving agent A, the condensation reagent and the catalyst to obtain a mixed solution;
(b) And (b) reacting the compound shown in the formula IV with the mixed solution obtained in the step (a) to obtain a mixed solution.
The mixing time of step (a) may be 1 to 24h, preferably 1h.
In the step (b), the temperature of the mixed solution obtained in the step (a) before mixing with the compound shown in the formula IV is preferably-10-25 ℃, for example, 0 ℃.
After the reaction in the step (b) is completed, heating the mixed solution to 25 ℃.
In the step (b), the compound shown as the formula IV is mixed with the mixed solution in the step (a) in a dropwise manner.
The invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps:
(1) In a solvent, carrying out condensation reaction on a compound shown as a formula IV and a resolving agent shown as a formula A to obtain a compound shown as a formula VI;
(2) In a solvent, in the presence of alkali, carrying out hydrolysis reaction on the compound shown as the formula VI;
in the step (1), the conditions and parameters of the preparation method of the compound shown in the formula VI are as described in any one of the invention.
In step (2), the base may be a conventional base for hydrolysis of such compounds in the art, preferably an inorganic base such as sodium hydroxide.
In step (2), the base is preferably added as an aqueous solution.
In step (2), the base may be used in a mass concentration which is conventional in the art for such hydrolysis reactions, preferably 5 to 30%, for example 10%.
The mass concentration is the mass percentage of the solute in the solution.
In step (2), the ratio of the amount of the base to the amount of the substance of the compound of formula VI may be an amount conventionally used in the art for hydrolysis of such compounds, preferably 2 to 10, for example 4.17.
In step (2), the solvent may be a solvent commonly used in the art for hydrolysis reactions, preferably an ethereal solvent, more preferably tetrahydrofuran.
In step (2), the reaction time may be a reaction time conventional in the art for hydrolysis reactions, preferably 0.5 to 24h, for example 5h.
In the step (2), the hydrolysis reaction may further include the following post-treatment operations: separating the organic phase from the aqueous phase, washing the organic phase and concentrating; the separation of the organic phase, washing and concentration can be carried out according to methods customary in the art.
In the preparation method of the compound shown in the formula I, the preparation method of the compound shown in the formula IV comprises the following steps:
and (3) carrying out reduction reaction on the compound shown as the formula III and a reducing agent in a solvent.
In the preparation method of the compound shown in the formula IV, the reduction reaction can be carried out in a protective gas atmosphere, and the protective gas is preferably nitrogen.
In the preparation method of the compound shown in formula IV, the reducing agent can be a conventional reducing agent in the art for such reduction reaction, preferably lithium borohydride, sodium cyanoborohydride or borane, such as sodium borohydride.
In the preparation method of the compound shown as the formula IV, the amount ratio of the reducing agent to the substance shown as the formula III can be the conventional amount in the field for the reduction reaction, and preferably (1-4): 1, such as 1:1.
In the preparation method of the compound shown in the formula IV, the ratio of the amount of the substance shown in the formula III to the volume of the solvent can be the conventional amount in the reduction reaction in the field, and is preferably (0.28-1.94) mol/L, such as 1.30mol/L.
In the preparation method of the compound shown in formula IV, the solvent may be a conventional solvent for such reduction reaction in the art, and is preferably an alcohol or an ether, such as tetrahydrofuran, methanol or ethanol.
In the preparation method of the compound shown in formula IV, the reaction temperature can be the conventional reaction temperature of the reduction reaction in the field, and is preferably 0-40 ℃, for example 10 ℃.
In the preparation method of the compound shown in the formula IV, the reaction time can be the conventional reaction time of the reduction reaction in the field, and is preferably 0.5-5h, for example 3h.
In the preparation method of the compound shown as the formula IV, the reduction reaction can be followed by post-treatment, wherein the post-treatment comprises the steps of sequentially carrying out alcohol quenching reaction, adding saturated potassium carbonate solution, heating and refluxing, cooling to normal temperature, separating out an organic phase, and carrying out spin-drying concentration to obtain the compound shown as the formula IV; the alcohol is preferably methanol.
In the preparation method of the compound shown in the formula I, the preparation method of the compound shown in the formula III comprises the following one or two methods:
the first method comprises the following steps: carrying out substitution reaction on a compound shown as a formula II in a solvent in the presence of sodium hydride and acetonitrile;
the second method comprises the following steps:
(i) In the presence of alkali, carrying out hydrolysis reaction on the compound shown as the formula V in the recrystallization mother liquor, and separating a water phase and an organic phase;
(ii) (ii) subjecting the organic phase of step (i) to an oxidation reaction with an oxidant in a solvent;
in the first method, the ratio of the amount of the compound represented by the formula II to the amount of the sodium hydride is preferably 1 (1.2-2.0), more preferably 1.
In the first method, the mass ratio of the compound shown in the formula II to the acetonitrile is preferably 1 (1.2-3), more preferably 1.6.
In the first method, the ratio of the amount of the substance of the compound represented by the formula II to the volume of the solvent is preferably (0.32-0.64) mol/L, and more preferably 0.52mol/L.
In the first method, the temperature of the substitution reaction is preferably 50 to 65 ℃, and more preferably 65 ℃.
In the first method, the reaction time of the substitution reaction is preferably 10 to 24 hours, and more preferably 15 to 18 hours.
In the first method, after the substitution reaction is finished, post-treatment may be further included.
The post-treatment may further comprise the steps of:
(1) After the substitution reaction is finished, quenching the reaction by using isopropanol and concentrating;
(2) Extracting the product with water and tert-butyl ether, taking the aqueous phase;
(3) Adjusting the pH value of the water phase to 1-2 by concentrated hydrochloric acid; the mass concentration of the concentrated hydrochloric acid is 37%;
(4) Extracting the product with dichloromethane, collecting organic phase, and concentrating.
In the second method, the base is preferably an inorganic base, and more preferably sodium hydroxide.
In the second method, the base is preferably added in the form of an aqueous solution.
In the second method, the mass concentration of the alkali is preferably 5 to 15%, and more preferably 10%.
In the second method, the reaction temperature of the hydrolysis reaction is preferably 20 to 30 ℃, and more preferably 25 ℃.
In the second method, the reaction time of the hydrolysis reaction is preferably 0.5 to 3 hours, and more preferably 1 hour.
In the second method, the oxidant can be hydrogen peroxide or m-chloroperoxybenzoic acid, and hydrogen peroxide is more preferable.
In the second method, the oxidizing agent is preferably added in the form of an aqueous solution.
In the second method, the mass concentration of the oxidizing agent is preferably 15 to 30%, and more preferably 30%.
In the second method, the solvent used in the oxidation reaction is preferably a chlorinated hydrocarbon, and more preferably dichloromethane.
In the second method, the reaction temperature of the oxidation reaction is preferably-10 to 10 ℃, and more preferably 0 ℃.
In the second method, the reaction time of the oxidation reaction is preferably 0.5 to 3.5 hours, and more preferably 3 hours.
In the second method, after the oxidation reaction is finished, the reaction product is preferably quenched by sodium thiosulfate, and more preferably by an aqueous solution of sodium thiosulfate; the mass concentration of the aqueous sodium thiosulfate solution is preferably 5 to 15%, for example, 10%.
In the preparation method of the compound shown in the formula I, the preparation method of the compound shown in the formula II comprises the following steps:
and (3) performing esterification reaction on the cyclopentanecarboxylic acid and thionyl chloride in methanol.
In the preparation method of the compound shown in the formula II, the ratio of the amount of substances of the cyclopentanecarboxylic acid to the methanol can be 1: (1-2), e.g., 1.
In the preparation method of the compound shown in the formula II, the methanol is a solvent and participates in the reaction.
In the preparation method of the compound shown in the formula II, the ratio of the substances of the cyclopentanecarboxylic acid to the thionyl chloride is 1 (0.01-1), for example, 1.
In the preparation method of the compound shown in the formula II, the reaction temperature of the esterification reaction can be 50-70 ℃, preferably 70 ℃.
In the preparation method of the compound shown in the formula II, the reaction time of the esterification reaction can be 2-10h, preferably 6h.
In the preparation method of the compound shown in the formula II, the esterification reaction can further comprise the following post-treatment: quenching with sodium carbonate aqueous solution, and separating organic layer.
In the preparation method of the compound shown in the formula I, the preparation method of the resolving agent shown in the formula A comprises the following steps:
in the presence of acid, carrying out acidification reaction on the water phase in the post-treatment operation in the step (2) of the preparation method of the compound shown in the formula I, the water phase in the second step (I) of the preparation method of the compound shown in the formula III or a mixed solution of the water phase and the water phase;
the acid is preferably sulfuric acid or hydrochloric acid, more preferably hydrochloric acid.
The reaction temperature of the acidification reaction is preferably, more preferably 25 ℃.
In the invention, the compound shown as the formula I is prepared by taking cyclopentanecarboxylic acid as a raw material, and the specific reaction is as follows:
the preparation method of the compounds shown in the formulas I to VI has the conditions and parameters as described in any one of the invention.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: a new preparation method of a ruxolitinib intermediate compound I and a corresponding intermediate are provided, and the compound I with the ee value of more than 98% is efficiently prepared by the preparation method and the corresponding intermediate; the related preparation method has high yield, stable corresponding intermediate, and repeated resolution of the compound, and can realize the optimization of material utilization.
Drawings
FIG. 1 is a graph of the retention time of (S) -3-cyclopentyl-3-hydroxypropionitrile standards by GC;
FIG. 2 is a graph showing retention times of the compound I obtained in example 4 and example 5 by GC.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The detection method comprises the following steps:
1. nuclear magnetic test conditions for compounds
The instrument model is as follows: bruker 400M
Frequency: 400MHz
Solution: CDCl 3 。
2. The GC test conditions for the compounds are shown in table 1.
TABLE 1
3. The HPLC test conditions for the compounds are shown in table 2.
TABLE 2
4. The Mass Spectrometry (MS) test conditions for the compounds are shown in Table 3
TABLE 3
Example 1
Synthesis of methyl cyclopentanoate (II)
1.5kg (13.16 mol) of cyclopentanecarboxylic acid and 0.75kg (23.44mol, 0.94L) of methanol are added into a 3L three-necked bottle, mechanical stirring is started, 78g (0.66 mol) of thionyl chloride is slowly dripped into the bottle, the temperature is raised to 70 ℃ for refluxing for 6h, the reaction liquid is poured into 4.5kg of saturated sodium bicarbonate aqueous solution for quenching, stirring is carried out for 30min, standing and layering are carried out, and the product is obtained, wherein 1.6kg of methyl cyclopentanoate (II) is obtained, the yield is 95%, and the purity is 95.1% (GC).
[M+H] + ：129.1；
1 H-NMR(400MHz,CDCl 3 ):3.6(3H,s),2.70(1H,m),1.90(8H,m)。
Example 2
Synthesis of 3-oxo-3-cyclopentylpropanenitrile (III)
Under the protection of nitrogen, adding tetrahydrofuran 4.8kg (66.56mol, 6L) and sodium hydride 200g (5.00 mol) into a 10L three-necked flask, heating to 65 ℃, dropwise adding a mixed solution of methyl cyclopentanoate (II) 400g (3.125 mol) and acetonitrile 208g (5.07 mol) into the reaction flask under the condition of reflux, keeping the temperature for 15-18h at 65 ℃, cooling to 15 ℃, adding isopropanol 200g to quench the reaction, concentrating the reaction solution, adding water 2kg to dissolve, extracting impurities by using methyl tert-butyl ether 1.2kg, adjusting the pH of an aqueous phase to 1-2 by using concentrated hydrochloric acid, extracting products by using dichloromethane 2kg, and spin-drying a dichloromethane phase to obtain 3-oxo-3-cyclopentylpropionitrile (III) 410g with the yield of 96 percent and the purity of 97.2 percent (GC).
[M+H] + ：138.1；
1 H-NMR(400MHz,DMSO-d 6 ):4.10(2H,s),3.00(1H,m),1.90(8H,m)。
Example 3
Synthesis of 3-cyclopentyl-3-hydroxypropionitrile (IV)
Under the protection of nitrogen, 1.8kg (2.25L) of tetrahydrofuran and 400g (2.92 mol) of 3-oxo-3-cyclopentyl propionitrile (III) are added into a 3L reaction bottle, the temperature is reduced to 10 ℃, 110g (2.94 mol) of sodium borohydride is added in batches, the temperature is raised to 25 ℃, the temperature is kept for 3h, 400g of methanol is added dropwise for quenching reaction, the mixture is stirred for 30min, 1.2kg of saturated potassium carbonate is added, the mixture is heated and refluxed for 1h, the temperature is reduced to 25 ℃, standing and layering are carried out, and an organic phase is dried in a spinning mode to obtain 390g of 3-cyclopentyl-3-hydroxy propionitrile (IV), the yield is 97.5%, and the purity is 97.5% (GC).
[M+H] + ：140.1；
1 H-NMR(400MHz,DMSO-d 6 ):4.30(1H,brs),3.50(1H,m),2.70(2H,m),1.90(1H,m),1.85(8H,m)。
Example 4
The general method for reacting 3-cyclopentyl-3-hydroxypropionitrile (IV) with a resolving agent is as follows:
under the protection of nitrogen, dichloromethane (the mass of 5 times of 3-cyclopentyl-3-hydroxypropionitrile (IV)) is added into a three-necked bottle, a resolving agent A (1.2 eq), EDCI (1.2 eq) and DMAP (1.2 eq) are added, the reaction is carried out for 1h at 25 ℃, the reaction temperature is reduced to 0 ℃, 3-cyclopentyl-3-hydroxypropionitrile (IV) (1.0 eq) is added dropwise, the reaction is carried out for 2h after the dropwise addition, water (the mass of 3-cyclopentyl-3-hydroxypropionitrile (IV) is added, the reaction is quenched, the organic phase is kept stand and layered, the organic phase is washed once by 1N HCl aqueous solution (the mass of 3-cyclopentyl-3-hydroxypropionitrile (IV) is 3 times of HCl), the organic phase is washed once by saturated sodium bicarbonate solution (the mass of 3-cyclopentyl-3-hydroxypropionitrile (IV) is 3 times of sodium sulfate), the organic phase is washed once by salt, the anhydrous enantiomer is dried to obtain a diastereomer mixture, and the single isomer mixture is obtained by recrystallization of S.
When resolving agent A is N-acetyl-L-phenylalanine, the diastereoisomer mixture is the diastereoisomer mixture of compound V and compound VI, the diastereoisomer excess ratio (de value) is 0%, the mixture of compound V and compound VI is recrystallized in methyl tert-butyl ether (the mass of 3-cyclopentyl-3-hydroxypropionitrile (IV) is 6 times of that of the compound V) to obtain compound VI, the ee value of (S) -2-cyano-1-cyclopentylethylacetyl-L-phenylalanine (VI) is 99.1 by HPLC (high performance liquid chromatography), and the recrystallization mother liquor is concentrated to obtain the crude product of compound V.
Comparing the product of compound VI hydrolyzed by example 5 with the standard product of (S) -3-cyclopentyl-3-hydroxypropionitrile, and determining the recrystallization result to be the compound shown in formula VI by GC test and keeping the retention time consistent with that of the (S) -3-cyclopentyl-3-hydroxypropionitrile shown in figures 1 and 2; and (5) comparing a product obtained after the hydrolysis of the crude product obtained after the concentration of the recrystallization residual mother liquor with the (R) -3-cyclopentyl-3-hydroxypropionitrile standard substance, and determining that the structure of the crude product obtained after the concentration of the recrystallization residual mother liquor is shown as a formula V.
The standard compound I and the standard (R) -3-cyclopentyl-3-hydroxypropionitrile are prepared by the selective reduction of 3-oxo-3-cyclopentyl propionitrile (III) with R-CBS IN patent IN202021005413, according to the description of the patent, after the compound III is reduced with R-CBS, the main product is the compound I, and the byproduct is mainly (R) -3-cyclopentyl-3-hydroxypropionitrile.
Specific data are shown in table 4:
TABLE 4 resolution of different resolving agents
Compound VI, [ M + H] + ：329.2；
1 H-NMR(400MHz,DMSO-d6):7.51(m,5H),5.22(m,1H),4.95(m,1H),3.50(1H,m),3.45(dd,1H),3.20(dd,1H),2.70(2H,m),2.15(s,3H),1.90(1H,m),1.85(8H,m)。
Compound V, [ M + H ]] + ：329.2；
1 H-NMR(400MHz,DMSO-d6):7.51(m,5H),5.22(m,1H),4.80(m,1H),3.50(1H,m),3.45(dd,1H),3.20(dd,1H),2.70(2H,m),2.15(s,3H),1.90(1H,m),1.85(8H,m)。
Remarking: the ee value is the (S) -3-cyclopentyl-3-hydroxypropionitrile (I) obtained in the final hydrolysis.
Example 5
Synthesis of (S) -3-cyclopentyl-3-hydroxypropionitrile (I)
Adding 100g (0.3 mol) of 2-methyltetrahydrofuran (S) -2-cyano-1-cyclopentylethylacetyl-L-phenylalanine (VI) into a 1L three-necked flask, starting stirring, slowly dropwise adding 500g (1.25 mol) of 10% sodium hydroxide aqueous solution, reacting at 25 ℃ for 5h, standing to separate an organic phase, washing once with 500g of saturated saline, and spin-drying the organic phase to obtain 39g of (S) -3-cyclopentyl-3-hydroxypropionitrile (I), wherein the yield is 93%, and the purity is 99.2% (GC).
[M+H] + ：140.1；
1 H-NMR(400MHz,DMSO-d 6 ):4.30(1H,brs),3.50(1H,m),2.70(2H,m),1.90(1H,m),1.85(8H,m)。
Example 6
Oxidative recovery of (R) -2-cyano-1-cyclopentylethylacetyl-L-phenylalanine (V)
500g of the mother liquor MTBE containing (R) -2-cyano-1-cyclopentylethylacetyl-L-phenylalanine (V) and (S) -2-cyano-1-cyclopentylethylacetyl-L-phenylalanine (VI) remaining after recrystallization in example 4 was charged into a 1L three-necked flask, 500g of a 10% aqueous sodium hydroxide solution was slowly added dropwise with stirring, reacted at 25 ℃ for 5 hours, the organic phase was allowed to stand and separate, washed once with 500g of saturated brine, and the organic phase was dried by spinning to give 30g of crude 3-cyclopentyl-3-hydroxypropionitrile (IV).
Dissolving the crude product of 3-cyclopentyl-3-hydroxypropionitrile (IV) by using 500g of dichloromethane, cooling to 0 ℃, dropwise adding 30% hydrogen peroxide to 50g, reacting for 3h, slowly dropwise adding 10% sodium thiosulfate aqueous solution to quench, standing for layering, washing an organic phase by using saturated sodium bicarbonate for 1 time, washing by using saline for 1 time, and performing spin drying to obtain 25g of a recovered product of 3-oxo-3-cyclopentylpropionitrile (III), wherein the yield is 83% and the purity is 95% (GC).
[M+H] + ：138.1；
1 H-NMR(400MHz,DMSO-d 6 ):4.10(2H,s),3.00(1H,m),1.90(8H,m)。
Example 7
Recovery of the resolving agent
1kg of hydrolyzed alkaline water phases obtained in the embodiment 5 and the embodiment 6 are combined, the pH value is adjusted to 1 by concentrated hydrochloric acid, a large amount of white solid is separated out from the aqueous phase, the filtration is carried out, a filter cake is pulped for 1 time by water, and an air-blast drying oven is dried at 60 ℃, so that 45g of a recovered resolving agent is obtained, the yield is 90%, and the purity is 99% (HPLC).
[M+H] + ：208.1；
1 H-NMR(400MHz,DMSO-d 6 ):12.60(1H,s),8.10(1H,d),7.30(5H,m),4.40(1H,m),3.00(1H,m),2.7(1H,m),1.70(3H,s)。
Comparative example 1
Synthesis of (S) -3-cyclopentyl-3-hydroxypropionitrile (I) the scheme of example-1 IN patent IN202021005413 was repeated, with the following specific steps:
under the protection of nitrogen, adding 10g of 3-oxo-3-cyclopentylpropionitrile (III) into a 500mL three-necked flask, adding 30mL of tetrahydrofuran, adding 1.01g R-CBS catalyst, controlling the temperature to be 20-30 ℃, slowly dropwise adding 110mL of 1M borane tetrahydrofuran complex, preserving the temperature for 30min, adding 50mL of water and 50mL of ethyl acetate after the reaction is finished, washing an organic phase once with 30mL of brine, drying with anhydrous sodium sulfate, and spin-drying to obtain 8g of the product with the yield of 80%, wherein the ee value is: 47% (HPLC).
Comparative example 2
Synthesis of (S) -3-cyclopentyl-3-hydroxypropionitrile (I), the procedure of example 1 in patent CN107674026 was repeated, and the specific steps were as follows:
under the protection of nitrogen, 150mL of tetrahydrofuran, 4.35mL of 1M R-CBS toluene solution and 44mL of 2M borane dimethyl sulfide are added into a 500mL three-necked bottle, the reaction temperature is cooled to 0 ℃,50mL of anhydrous tetrahydrofuran solution of 12g of 3-oxo-3-cyclopentyl propionitrile (III) is slowly dripped, after the dripping is finished, the reaction is carried out for 10-12 h at 25 ℃, the reaction is cooled to 0 ℃ after the completion, 50mL of methanol is added, the stirring is carried out for 30min, 250mL of toluene is added, 3 times of washing are carried out by 3X 100mL of 0.2M sulfuric acid aqueous solution, 3 times of washing are carried out by 3X 100mL of water, the organic phase is dried by anhydrous sodium sulfate, 9.5g is obtained by spin drying, the yield is 79%, and the ee value: 63% (HPLC).
Comparative example 3
Synthesis of (S) -3-cyclopentyl-3-hydroxypropionitrile (I) the procedure of example 2 in patent CN107674026 was repeated, with the following specific steps:
under the protection of nitrogen, 150mL of tetrahydrofuran, 4.35mL of 1M R-CBS toluene solution and 33mL of 2M borane dimethyl sulfide are added into a 500mL three-necked flask, the reaction temperature is cooled to 0 ℃,50mL of anhydrous tetrahydrofuran solution of 8.93g of 3-oxo-3-cyclopentyl propionitrile (III) is slowly dripped, after the dripping is finished, the reaction is carried out for 10 to 12 hours at 25 ℃, the reaction is cooled to 0 ℃ after the reaction is finished, 50mL of methanol is added, the stirring is carried out for 30min, 250mL of toluene is added, 3 times of washing are carried out by 3 times of 0.2M sulfuric acid aqueous solution, 3 times of 100mL of water-free sodium sulfate of organic phase is dried, and the drying is carried out to obtain 7.5g, the yield is 83%, and the ee value: 49% (HPLC).
Claims (10)
1. A compound of formula VI, a compound of formula V, or a diastereomeric mixture of both:
2. a preparation method of a compound shown as a formula VI or a compound shown as a formula V is characterized by comprising the following steps:
in a solvent, carrying out condensation reaction on a compound shown as a formula IV and a resolving agent shown as a formula A to obtain a compound shown as a formula VI or a compound shown as a formula V;
the compound shown in the formula IV is a mixture of a compound shown in a formula IV 'and a compound shown in a formula IV';
3. the method of claim 2, wherein the method of making satisfies one or more of the following:
(1) the molar ratio of the resolving agent A to the compound shown in the formula IV is (0.9-1.5) to 1, preferably 1.2;
(2) the solvent is an aprotic solvent, preferably dichloromethane;
(3) the mass ratio of the solvent to the compound shown in the formula IV is (1-20) to 1, preferably 5:1;
(4) the condensation reaction is carried out in the presence or absence of a condensing agent, wherein, when the condensing agent is present,
the molar ratio of the condensing agent to the compound of formula IV is preferably (0.9-1.5) 1, for example 1.2;
and/or, the condensing agent is preferably DCC, CDI, EDCI, HATU or HBTU, e.g. EDCI;
preferably, the condensation reaction is carried out in the presence or absence of a catalyst, wherein, when the catalyst is present,
the molar ratio of the catalyst to the compound of formula IV is preferably (0.1-1.5) 1, e.g. 1.2;
and/or, the catalyst is preferably HOBt or DMAP, such as DMAP;
(5) the condensation reaction is carried out in a protective gas atmosphere, and the protective gas is preferably nitrogen;
(6) the reaction time of the condensation reaction is 1-24h, for example 2h;
(7) the condensation reaction also comprises post-treatment after the condensation reaction is finished,
preferably, the post-treatment further comprises recrystallization, wherein a product obtained after the condensation reaction is finished is recrystallized in a solvent to obtain a recrystallized solid and a recrystallization mother liquor;
the solvent is preferably an ester solvent, a halogenated hydrocarbon solvent, an alcohol solvent, a ketone solvent, a nitrile solvent or an ether solvent; further preferred is ethyl acetate, dichloromethane, methanol, ethanol, acetone, acetonitrile or methyl tert-butyl ether, such as methyl tert-butyl ether or dichloromethane;
and/or the mass ratio of the mass of the product obtained after the condensation reaction to the mass of the solvent is preferably 1: (2-10), for example 1:6.
4. The process according to claim 3, wherein the condensation reaction is carried out in the presence of the condensation agent and the catalyst;
the preparation method preferably comprises the following steps:
(a) In the solvent, mixing the resolving agent A, the condensation reagent and the catalyst to obtain a mixed solution;
(b) Reacting the compound shown in the formula IV with the mixed solution obtained in the step (a);
preferably, the preparation method satisfies one or more of the following conditions:
(1) the mixing time of step (a) is 1-24h, e.g. 1h;
(2) in the step (b), the temperature of the mixed solution obtained in the step (a) before being mixed with the compound shown as the formula IV is-10-25 ℃, for example, 0 ℃;
(3) after the reaction in the step (b) is finished, heating to 25 ℃;
(4) and (b) mixing the compound shown as the formula IV with the mixed solution in the step (a) in a dropwise manner.
5. A preparation method of a compound shown as a formula I is characterized by comprising the following steps:
(1) In a solvent, carrying out condensation reaction on a compound shown as a formula IV and a resolving agent shown as a formula A to obtain a compound shown as a formula VI;
(2) In a solvent, in the presence of alkali, carrying out hydrolysis reaction on the compound shown as the formula VI;
6. a process for the preparation of a compound of formula I as claimed in claim 5,
in step (1), the preparation method of the compound shown in the formula VI has the conditions and parameters as in any one of claims 1-4;
in the step (2), the hydrolysis reaction satisfies one or more of the following conditions:
(1) the alkali is inorganic alkali, preferably sodium hydroxide;
(2) the adding mode of the alkali is aqueous solution;
(3) the mass concentration of the alkali is 5-30%, preferably 10%;
(4) the ratio of the amount of the base to the amount of the substance represented by the formula VI is 2-10, preferably 4.17;
(5) the solvent is an ether solvent, preferably tetrahydrofuran;
(6) the reaction time of the hydrolysis reaction is 0.5 to 24 hours, for example 5 hours;
(7) the hydrolysis reaction also comprises the following post-treatment operations: the organic and aqueous phases were separated, the organic phase was washed and concentrated.
7. The process of claim 6, wherein the compound of formula IV is prepared by a process comprising the steps of:
in a solvent, carrying out a reduction reaction on a compound shown as a formula III in the presence of a reducing agent;
preferably, the preparation method of the compound shown in the formula IV satisfies one or more of the following conditions:
(1) the reduction reaction is carried out in a protective gas atmosphere, and the protective gas is preferably nitrogen;
(2) the reducing agent is lithium borohydride, sodium cyanoborohydride or borane, such as sodium borohydride;
(3) the ratio of the amount of reducing agent to the amount of compound of formula III is (0.5-4) 1, e.g., 1:1;
(4) the ratio of the amount of the compound shown in the formula III to the volume of the solvent is (0.28-1.94) mol/L, such as 1.30mol/L;
(5) the solvent is alcohols or ethers, such as tetrahydrofuran, methanol or ethanol;
(6) the reaction temperature is 0-40 ℃, e.g., 10 ℃;
(7) the reaction time is 0.5 to 5h, for example 3h.
8. The process of claim 7, wherein the process for preparing the compound of formula III comprises one or more of the following steps:
the first method comprises the following steps: carrying out substitution reaction on a compound shown as a formula II in a solvent in the presence of sodium hydride and acetonitrile;
the second method comprises the following steps:
(i) Hydrolyzing the compound represented by the formula V in the recrystallization mother liquor in claim 3 in the presence of a base, and separating an aqueous phase and an organic phase;
(ii) (ii) subjecting the organic phase of step (i) to an oxidation reaction with an oxidant in a solvent;
preferably, in the first method, the compound shown in formula III is prepared by one or more of the following methods:
(1) the mass ratio of the compound shown as the formula II to the sodium hydride is 1 (1.2-2.0), preferably 1;
(2) the mass ratio of the compound shown as the formula II to the acetonitrile is 1 (1.2-3), preferably 1.6;
(3) the ratio of the amount of the substance of the compound shown in the formula II to the volume of the solvent is (0.32-0.64) mol/L, and preferably 0.52mol/L;
(4) the temperature of the substitution reaction is 50-65 ℃, preferably 65 ℃;
(5) the reaction time of the substitution reaction is 10-24h, preferably 15-18h;
preferably, in the second method, the preparation method of the compound shown in the formula III satisfies one or more of the following conditions:
(1) the alkali is inorganic alkali, preferably sodium hydroxide;
(2) the base is added in the form of an aqueous solution;
(3) the mass concentration of the alkali is 5-15%, preferably 10%;
(4) the reaction temperature of the hydrolysis reaction is 20-30 ℃, and preferably 25 ℃;
(5) the reaction time of the hydrolysis reaction is 0.5-3h, preferably 1h;
(6) the oxidant is hydrogen peroxide or m-chloroperoxybenzoic acid, preferably hydrogen peroxide;
(7) the oxidant is added in the form of an aqueous solution;
(8) the mass concentration of the oxidant is 15-30%, preferably 30%;
(9) in the oxidation reaction, the used solvent is chlorohydrocarbon, preferably dichloromethane;
the reaction temperature for the oxidation reaction in r is-10-10 ℃, preferably 0 ℃;
9. The process of claim 8, wherein the compound of formula II is prepared by a process comprising the steps of:
in methanol, performing esterification reaction on cyclopentanecarboxylic acid and thionyl chloride;
preferably, the preparation method of the compound shown in the formula II satisfies one or more of the following conditions:
(1) the ratio of the amount of substances of the cyclopentanecarboxylic acid to the methanol is 1: (1-2), e.g., 1;
(2) the ratio of the amount of said substance of said cyclopentanecarboxylic acid to said thionyl chloride is 1 (0.01-1), e.g. 1;
(3) the reaction temperature of the esterification reaction is 50-70 ℃, and preferably 70 ℃;
(4) the reaction time of the esterification reaction is 2-10h, preferably 6h.
10. A process for the preparation of a compound of formula I according to any one of claims 5 to 9, wherein the process for the preparation of a resolving agent of formula a comprises the steps of:
subjecting the aqueous phase of claim 6, the aqueous phase of claim 8, or a mixture thereof to an acidification reaction in the presence of an acid;
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107759601A (en) * | 2016-08-23 | 2018-03-06 | 苏州旺山旺水生物医药有限公司 | A kind of preparation method of JAK inhibitor and its salt |
| US20190023712A1 (en) * | 2015-12-31 | 2019-01-24 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Synthesis process of ruxolitinib |
| CN113292569A (en) * | 2021-05-25 | 2021-08-24 | 常州制药厂有限公司 | Preparation method of JAK inhibitor |
| WO2022040180A1 (en) * | 2020-08-18 | 2022-02-24 | Incyte Corporation | Process and intermediates for preparing a jak inhibitor |
| CN114456181A (en) * | 2022-02-21 | 2022-05-10 | 浙江乐普药业股份有限公司 | Preparation method of luccotinib |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190023712A1 (en) * | 2015-12-31 | 2019-01-24 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Synthesis process of ruxolitinib |
| CN107759601A (en) * | 2016-08-23 | 2018-03-06 | 苏州旺山旺水生物医药有限公司 | A kind of preparation method of JAK inhibitor and its salt |
| WO2022040180A1 (en) * | 2020-08-18 | 2022-02-24 | Incyte Corporation | Process and intermediates for preparing a jak inhibitor |
| CN113292569A (en) * | 2021-05-25 | 2021-08-24 | 常州制药厂有限公司 | Preparation method of JAK inhibitor |
| CN114456181A (en) * | 2022-02-21 | 2022-05-10 | 浙江乐普药业股份有限公司 | Preparation method of luccotinib |
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