CN114315494B - Preparation method of (S) -2-methylazetidine hydrochloride - Google Patents
Preparation method of (S) -2-methylazetidine hydrochloride Download PDFInfo
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Abstract
The application relates to the technical field of organic synthesis, in particular to a preparation method of an intermediate (S) -2-methylazetidine hydrochloride of a ketohexokinase inhibitor, which comprises the following steps: esterifying 1, 3-butanediol with methanesulfonyl chloride to obtain a compound of formula (I), cyclizing the compound of formula (I) with S-phenethylamine to obtain a mixture of a compound of formula (II) and a compound of formula (III), refining and resolving the mixture to obtain the compound of formula (II), and deprotecting the compound of formula (II) to obtain the compound of formula (IV). The application provides a simple and convenient industrialized production route for the intermediate of the hexulokinase inhibitor, and has the advantages of low price of the initial raw materials, simple and convenient reaction, higher resolution yield and lower cost, and can realize stable industrialized production and preparation.
Description
Technical Field
The application belongs to the technical field of organic synthesis, and in particular relates to a preparation method of an intermediate (S) -2-methylazetidine hydrochloride of a ketohexokinase inhibitor.
Background
Diabetes is a major public health concern due to its increasing prevalence and associated health risks. The disease is characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. The two major forms of diabetes are type 1 and type 2. Type 1 diabetes (T1D), type 2 diabetes (T2D) usually begins with insulin resistance when the body's immune system damages pancreatic beta cells or when insulin production is insufficient to maintain acceptable glucose levels. Of these, T2D is most often associated with hyperglycemia and insulin resistance.
Current drug therapies for T2D are altered in strategies to include agents that increase insulin secretion, affect insulin activity, alter lipid metabolism, and reduce nutrient absorption. Inhibiting the KHK metabolism of fructose provides a new alternative to current therapeutic strategies. KHK is the primary enzyme in fructose metabolism, catalyzing the conversion of fructose to fructose-1-phosphate (FIP). It has been shown that endogenously produced fructose can contribute to insulin resistance and hepatic steatosis in hyperglycemic conditions (lanospa, M.A, nature Comm,4,2434,2013). Thus, inhibition of KHK is expected to be beneficial for many diseases in which alterations in either or both endogenous or ingested fructose are designed.
The test on the KHK inhibitor shows that the hexulokinase inhibitor has good effect on inhibiting KHK, wherein (S) -2-methylazetidine hydrochloride is used as an intermediate of the hexulokinase inhibitor, and the synthesis process and the development of raw material cost of the hexulokinase inhibitor have very important significance.
The literature reports the synthesis of (S) -2-methylazetidine hydrochloride, mainly by the following methods:
the method comprises the following steps: WO2017059251A1, WO2018229629A1. The synthesis methods reported in the two patents are consistent, D-acridine-2-carboxylic acid is used as a starting material, amino is firstly protected, then the carboxylic acid is reduced to alcohol, the alcohol hydroxyl is esterified with chloromethyl sulfonic acid and then reduced, and finally the (S) -2-methylazetidine hydrochloride is obtained through debroc protection.
The disadvantage of this route is that: the initial chiral raw material D-acridine-2-carboxylic acid has high price, the yield of the second step is only 19%, and the cost is high, so that the method is not beneficial to industrial production.
The second method is as follows: US2017183328A1. This patent reports a method for synthesizing (S) -2-methylazetidine hydrochloride. The (S) -2-methylazetidine hydrochloride is prepared by taking (R) - (-) -1, 3-butanediol as a raw material, esterifying with chloromethyl sulfonic acid, then closing a ring with benzylamine, and finally debenzylating.
Compared with the method I, the method has the advantages that the raw material is replaced, the raw material price is slightly high, palladium hydroxide is needed, the raw material cost is high, the chiral purity of the ring-closed product is low, chiral reagent is needed to be split again, the operation is complex, the yield is low, and the method is not beneficial to industrial production.
Several of the methods reported in the above documents have high raw material costs and complicated operations, and thus it is required to find a low-cost route suitable for industrialization.
Disclosure of Invention
In order to solve the problems in the prior art, a more efficient synthesis method is sought, the production cost is reduced, further research on the synthesis steps of the compound is provided, a low-cost route suitable for industrial production is found, and a new synthesis method is provided for pharmaceutical enterprises at home and abroad.
The application provides a novel synthesis method of (S) -2-methylazetidine hydrochloride. Provides a new preparation method for the (S) -2-methylazetidine hydrochloride, has low price of initial raw materials, simple and convenient reaction, higher yield and lower cost, and can realize stable industrialized production and preparation.
In order to solve the technical problems, the application adopts the following technical scheme:
a process for the preparation of (S) -2-methylazetidine hydrochloride, comprising:
esterifying 1, 3-butanediol with methanesulfonyl chloride to obtain a compound of formula (I);
closing the ring of the compound of the formula (I) and S-phenethylamine to obtain a mixture of the compound of the formula (II) and the compound of the formula (III);
refining and resolving the mixture of the compound of the formula (II) and the compound of the formula (III) to obtain the compound of the formula (II);
deprotection of a compound of formula (II) to give a compound of formula (IV);
wherein the structural formulas of the compounds of formula (I) to (IV) are as follows:
in some embodiments, the preparation method specifically includes the following steps:
step 1), reacting raw material 1, 3-butanediol with methanesulfonyl chloride in a reaction solvent in the presence of alkali to obtain a compound shown in a formula (I);
step 2), the compound of the formula (I) reacts with S-phenethylamine in a ring closing way to obtain a mixture of the compound of the formula (II) and the compound of the formula (III);
step 3), refining and resolving the mixture of the compound of the formula (II) and the compound of the formula (III) to obtain the compound of the formula (II);
step 4), dissolving the compound shown in the formula (II) in a solvent, and carrying out deprotection reaction under the action of a catalyst to obtain the compound shown in the formula (IV).
In some embodiments, in step 1), the base is any one or more of triethylamine and pyridine.
In some embodiments, in step 1), the reaction solvent is one or more of ethyl acetate, dichloromethane, methanol;
the reaction temperature is 20-25 ℃, and the reaction time is 2-3h.
In some embodiments, in step 2), the reaction temperature is 40-50 ℃ and the reaction time is 8-10 hours.
In some embodiments, in step 3), the solvent used in the refining is one or more of methyl tert-butyl ether, ethyl acetate and n-hexane.
In some embodiments, in step 4), at least any one of the following is satisfied: the solvent is one or more of dichloromethane, methanol and ethanol; the reaction temperature is 20-25 ℃; the reaction time is 3-5h.
In some embodiments, in step 1), in step 4), the catalyst is selected from palladium on carbon.
In some embodiments, the synthetic route is as follows:
the beneficial effects are that: the preparation method of the intermediate (S) -2-methylazetidine hydrochloride of the hexulokinase inhibitor provided by the application has the advantages of low raw material price, simple and convenient reaction operation and high yield, and is beneficial to industrial production.
The method is characterized by comprising the following steps: cheap raw materials, simple and convenient reaction operation and higher reaction yield. Firstly, a novel synthesis method is provided, 1, 3-butanediol raceme is esterified and then is closed for resolution, the price of the raceme is low, and the cost can be greatly reduced; secondly, providing a resolution method, closing a ring by using S-phenethylamine and sulfonate to form a salt, wherein the proportion of non-corresponding isomers is 91:9; separating the non-corresponding isomers by a recrystallization method, wherein the operation is simple and the loss is small, so that the yield of two steps of ring closing resolution is 82%; finally, the palladium carbon is deprotected, and can be recycled, so that the cost is reduced, the operation is simplified, the waste of resources is avoided, and the three wastes are greatly reduced, thereby having great significance for developing the preparation method and the amplified production of the intermediate of the hexulokinase inhibitor.
Detailed Description
The application will be further described with reference to specific examples.
Abbreviation comparison table in the present application
| DCM | Dichloromethane (dichloromethane) |
| MTBE | Methyl tert-butyl ether |
| EA | Acetic acid ethyl ester |
| TEA | Triethylamine |
| HCl | Hydrogen chloride |
| 1 H-NMR | Nuclear magnetic resonance hydrogen spectrum |
| LC | Liquid phase analysis method |
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred methods and materials described herein are presented for illustrative purposes only.
The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.
Intermediate (S) -2-methylazetidine hydrochloride of ketohexokinase inhibitor, the chemical structural formula is as follows:
the preparation method comprises the following steps:
step 1), reacting raw material 1, 3-butanediol with methanesulfonyl chloride in a reaction solvent in the presence of alkali to obtain a compound shown in a formula (I);
step 2), the compound of the formula (I) reacts with S-phenethylamine in a ring closing way to obtain a mixture of the compound of the formula (II) and the compound of the formula (III);
step 3), refining and resolving the mixture of the compound of the formula (II) and the compound of the formula (III) to obtain the compound of the formula (II);
step 4), dissolving the compound shown in the formula (II) in a solvent, and carrying out deprotection reaction under the action of a catalyst to obtain the compound shown in the formula (IV).
The synthetic route is as follows:
embodiment one:
1, 3-butanediol (90 g,1 mol), triethylamine (130 g,1.3 mol) and DCM (1L) were added to the reaction flask, and methanesulfonyl chloride (350 g,3 mol) was added dropwise at room temperature. After the completion of the dropwise addition, the reaction was carried out at room temperature for 2 hours. After completion of the reaction, a saturated sodium chloride solution was added, washed with water, extracted with DCM (3×500 ml), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give crude product which was passed through a column to give 220g of the compound of formula (i) (yield 91%). 1 H NMR(CDCl 3 )δ:1.48-1.50(d,3H),2.06-2.10(m,2H),3.03-3.05(s,6H),4.32-4.35(t,2H),4.96-5.00(m,1H)。
Embodiment two:
s-phenethylamine (1187 g,9.8 mol) is added into a reaction bottle, the temperature is controlled to be lower than 45 ℃, a compound (460 g,2.8 mol) of a formula (I) is dropwise added, stirring is carried out for 1h at room temperature after the completion of the dropwise addition, then the temperature is increased to 45 ℃ for reacting for 10h (precipitating a large amount of solid), the ratio of a non-corresponding isomer compound of a formula (II) to a compound of a formula (III) is detected by LC to be 91:9, after the reaction is finished, filtering, combining organic phases, washing a separated liquid by water, adding HCl/EA (1.5L) solution, stirring into salt, filtering, recrystallizing MTBE, and filtering and drying to obtain 486g of a compound of a formula (II) (yield 82%).
Embodiment III:
the reaction flask was charged with the compound of formula (ii) (13.1 g,62 mmol), methanol (130 mL), 10% palladium on carbon (0.65 g), hydrogen displacement, hydrogen pressurization, reaction at room temperature until LC showed no starting material remaining, filtration, extraction of the filtrate twice with MTBE (100 mL x 2), and spin-drying gave 6.3g of the product of formula (iv) (yield 95%). 1 H NMR(400MHz,CDCl 3 )δ1.545(d,3H),2.295-2.317(m,1H),2.509-2.581(m,1H),3.881-4.025(m,2H),4.554-4.625(m,1H),9.4130(s,2H)。
The foregoing is only a preferred embodiment of the application, it being noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present application, and such modifications and adaptations are intended to be comprehended within the scope of the application.
Claims (9)
1. A process for the preparation of (S) -2-methylazetidine hydrochloride, comprising:
esterifying 1, 3-butanediol with methanesulfonyl chloride to obtain a compound of formula (I);
closing the ring of the compound of the formula (I) and S-phenethylamine to obtain a mixture of the compound of the formula (II) and the compound of the formula (III); wherein the ring closing reaction temperature is 40-50 ℃ and the reaction time is 8-10h;
refining and resolving the mixture of the compound of the formula (II) and the compound of the formula (III) to obtain the compound of the formula (II);
deprotection of a compound of formula (II) to give a compound of formula (IV);
wherein the structural formulas of the compounds of formula (I) to (IV) are as follows:
2. the method of manufacturing according to claim 1, comprising the steps of:
step 1), reacting raw material 1, 3-butanediol with methanesulfonyl chloride in a reaction solvent in the presence of alkali to obtain a compound shown in a formula (I);
step 2), the compound of the formula (I) reacts with S-phenethylamine in a ring closing way to obtain a mixture of the compound of the formula (II) and the compound of the formula (III);
step 3), refining and resolving the mixture of the compound of the formula (II) and the compound of the formula (III) to obtain the compound of the formula (II);
step 4), dissolving the compound shown in the formula (II) in a solvent, and carrying out deprotection reaction under the action of a catalyst to obtain the compound shown in the formula (IV).
3. The preparation method according to claim 2, wherein in the step 1), the base is one or more of triethylamine and pyridine.
4. The preparation method according to claim 2, wherein in step 1), the reaction solvent is one or more of ethyl acetate, dichloromethane and methanol.
5. The process according to claim 2, wherein in step 1), the reaction temperature is 20 to 25℃and the reaction time is 2 to 3 hours.
6. The preparation method according to claim 2, wherein in the step 3), the solvent used for refining is one or more of methyl tertiary butyl ether, ethyl acetate and n-hexane.
7. The preparation method according to claim 2, wherein in the step 4), the solvent is one or more of dichloromethane, methanol and ethanol.
8. The process according to claim 2, wherein in step 4), the reaction temperature is 20-25 ℃; the reaction time is 3-5h.
9. The process according to claim 2, wherein in step 4) the catalyst is selected from palladium on carbon.
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