CN115417794B - Preparation method of saxagliptin intermediate - Google Patents

Preparation method of saxagliptin intermediate Download PDF

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CN115417794B
CN115417794B CN202211149372.1A CN202211149372A CN115417794B CN 115417794 B CN115417794 B CN 115417794B CN 202211149372 A CN202211149372 A CN 202211149372A CN 115417794 B CN115417794 B CN 115417794B
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saxagliptin
tert
reaction
acetic acid
hydroxyadamantanone
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CN115417794A (en
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吴鹏程
祝瑞章
徐园
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Yangzhou Sanyao Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C07C313/06—Sulfinamides
    • 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
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a preparation method of a saxagliptin intermediate. The method comprises the following steps: step one: condensing hydroxyadamantanone acetic acid and (S) -tert-butyl sulfinamide in the presence of Lewis acid, and reducing the condensed hydroxyadamantanone acetic acid and (S) -tert-butyl sulfinamide under the action of a reducing agent to generate an intermediate (3); step two: and (3) dissolving the intermediate (3) in an acidic solution, removing the tertiary butyl sulfinyl protecting group, adjusting the pH to be alkaline, and adding BOC anhydride to generate the target compound saxagliptin intermediate (1). The method has the advantages of easily obtained raw materials, stable performance and mild reaction conditions, and the purity of the obtained product is up to more than 99 percent, and the yield of each step is up to more than 95 percent.

Description

Preparation method of saxagliptin intermediate
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of a saxagliptin intermediate.
Background
Saxagliptin intermediate, chemical name of N-t-butoxycarbonyl-3-hydroxy-1-adamantyl-D-glycine, CAS:361442-00-4 has chemical structure shown in the following formula:
saxagliptin intermediate (1)
Saxagliptin (saxagliptin), also known as An Lize, chemical name (1S, 3S, 5S) 2- [ (2S) 2-amino-2 (3-hydroxyadamantan-1-yl) acetyl ] -2-azabicyclo [3.1.0] hexane-3-carbonitrile, a novel anti-type 2 diabetes drug co-developed by Bris-tol-Myers Squibb and Astra Zeneca company, marketed in china 2011. The main action mechanism is to inhibit dipeptidyl peptidase IV (DPP-IV) reversibly, competitively and selectively, reduce the hydrolysis of glucagon-like peptide-1 (GLP-1), and increase the release of insulin so as to reduce blood sugar. Has the advantages of obvious hypoglycemic effect, small side effect, good patient compliance and high safety, and is widely paid attention once being marketed. Because the application and development prospects of the medicine are good, the research on the synthesis process of important intermediates of the medicine also draws great attention to the market.
The chemical synthesis of saxagliptin can be obtained by only condensation, dehydration and deprotection of (S) -N-t-butoxycarbonyl-3-hydroxy-1-adamantine glycine (1) and (1S, 3S, 5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide salt. The saxagliptin intermediate (1) is a chiral compound, the construction of chiral centers is a key step, and the preparation method mainly comprises three steps:
(1) The chemical resolution method is that U.S. Pat. No. 3,182 reports that the alpha-position of adamantane acetic acid is brominated and then led to 3-hydroxyl under the condition of mixed acid, then the alpha-position is subjected to ammonolysis reaction and amino Boc protection to obtain N-tert-butoxycarbonyl-3-hydroxyl-1-adamantane glycine, and finally chemical resolution is carried out to obtain (1); this process results in the waste of another configurational compound.
(2) Semisynthesis, adv. Synth. Catalyst, 2007, 349 (8-9): 1369-1378. 2- (3-hydroxy adamantan-1-yl) -2-oxo acetic acid is prepared by taking adamantane carboxylic acid or bromoadamantane as a starting material, the 2- (3-hydroxy adamantan-1-yl) -2-oxo acetic acid is subjected to catalytic reduction by phenylalanine dehydrogenase after ammoniation to obtain (S) -3-hydroxy-1-adamantan glycine, and finally Boc protection is carried out to obtain (1); the enzyme catalysis condition is harsh, the yield is not high, and the large-scale production is difficult.
(3) The stereoselective synthesis is described in J.Med.chem.,2004,8 (15): 5025-5037. Adamantanecarboxylic acid is reduced and selectively oxidized to give adamantaneformaldehyde, which is condensed with (R) -2 phenylglycinol and then reacted with cyano groups, followed by hydrolysis, catalytic hydrogenation, and protection with amino Boc to give (S) -N-t-butoxycarbonyl adamantaneglycine, which is oxidized with potassium permanganate to give (1). The steps are long, high-risk reaction exists, and the selectivity is low.
In view of the above, there is a need for an improvement in the preparation process of alogliptin intermediate (1) in the prior art to solve the above-mentioned problems.
Disclosure of Invention
The invention aims to: the invention aims to disclose a preparation process of a saxagliptin intermediate (1), wherein a starting raw material 2- (3-hydroxy-1-adamantane) -2-oxo acetic acid (CAS: 709031-28-7) is easy to obtain and stable in performance, the process comprises two steps, namely, condensation reaction, simple treatment, no separation and purification are needed, the process can be directly used for next reduction, the requirements on equipment and operation are reduced, the risk of influencing the quality of raw materials is reduced, the operation is simple, the process period is short, and the product purity is high, so that the process is suitable for industrial production; step two, desulfonating group and upper BOC protecting group; the acidolysis is also simple, and then the next reaction is directly carried out, so that the emission of three wastes is reduced, and the environmental protection is facilitated.
The technical scheme is as follows: the preparation method of the saxagliptin intermediate provided by the invention comprises the following steps of:
specifically, the method comprises the following steps:
step one: condensing hydroxyadamantanone acetic acid and (S) -tert-butyl sulfinamide in the presence of Lewis acid, and reducing the condensed hydroxyadamantanone acetic acid and (S) -tert-butyl sulfinamide under the action of a reducing agent to generate an intermediate (3);
step two: and (3) dissolving the intermediate (3) in an acidic solution, removing the tertiary butyl sulfinyl protecting group, adjusting the pH to be alkaline, and adding BOC anhydride to generate the target compound saxagliptin intermediate (1).
The total reaction flow is as follows:
specifically, in the first step, the Lewis acid used in the condensation reaction is a titanium reagent, including tetraisopropyl titanyl and titanium tetrachloride; or the lewis acid is a tin reagent comprising: tin tetrachloride, tin dichloride.
Specifically, in the first step, the reducing agent is a boron reagent including sodium borohydride and potassium borohydride.
Specifically, in the first step, the tertiary butyl sulfinamide used in the condensation reaction is in the (S) configuration, and the molar ratio of the tertiary butyl sulfinamide to the ketone is as follows: the sulfenamide is 1:1-5. Preferably 1:2.
Specifically, in the second step, the acid is hydrochloric acid, sulfuric acid or phosphoric acid, and the concentration is 1mol/L-4mol/L; preferably 2mol/L; the alkali used is sodium hydroxide and potassium hydroxide.
Specifically, in the second step, the solvent is a high-polarity solvent including dioxane, dimethylformamide and tetrahydrofuran. Dioxane is preferred.
Specifically, in the second step, the control range of the alkaline pH is 7-13. The pH is preferably controlled in the range of 9-12.
Further, the best scheme of the invention is as follows:
step one: toluene is taken as a solvent, hydroxyadamantanone acetic acid is mixed with (S) -tert-butylsulfinamide, condensation reaction is carried out in the presence of tetraisopropyl titanyl, reaction is carried out for 24 hours at room temperature, then the reaction is finished, reducing agent sodium borohydride is added, quenching is carried out after the reaction is finished for 1 hour, and chiral intermediate (3) is generated through operations such as extraction, drying, concentration and the like, and the next reaction is directly carried out.
Step two: dissolving the intermediate (3) in a high-polarity solvent, adding strong acid, removing tert-butylsulfinyl protecting group, adjusting the pH to 9-12 with alkali, and adding BOC anhydride to obtain the saxagliptin intermediate (1).
The beneficial effects are that: (1) The invention discloses a novel chiral synthesis process of a saxagliptin intermediate (1), wherein the chiral purity of a product of the preparation process is up to more than 99%, and the yield is up to more than 95%; (2) The starting material 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid (CAS: 709031-28-7) is readily available and stable in performance; (3) The method has the advantages of mild reaction conditions, simple treatment, no need of separation and purification after the condensation reaction in the first step, direct application to the next reduction, reduction of equipment and operation requirements, reduction of the risk of influencing the quality of the raw materials, simple operation, short process period and high product purity, and is suitable for industrial production; the acidolysis of the second step is also carried out after simple treatment, and the next reaction is directly carried out; and (4) the emission of three wastes is reduced, and the environmental protection is facilitated.
Drawings
FIG. 1 is a process diagram of the preparation of saxagliptin intermediate (1) in the present invention;
FIG. 2 is an HPLC chart of saxagliptin intermediate (2) prepared in example one;
fig. 3 is an HPLC profile of saxagliptin intermediate (2) prepared in example two.
Detailed Description
The following is a detailed description of the present invention, but the scope of the present invention is not limited to the examples.
Example 1:
the embodiment discloses a preparation method of a saxagliptin intermediate (1), which comprises a first step and a second step, wherein the total reaction flow is as follows:
step one: after condensation of hydroxyadamantanone acetic acid with (S) -tert-butylsulfinamide, reduction yields chiral intermediate (3) as follows:
to a 25mL round bottom flask was added 10mL of dry dichloromethane, and (R) -tert-butylsulfinamide (5.0 mmol), hydroxyadamantanone-base acetic acid (6.0 mmol), tetraisopropyl titanyl (2.97 mL,10.0 mmol). Stirring at room temperature for 24 hours, adding 5mL of saturated salt water for quenching, filtering by diatomite, evaporating the solvent under reduced pressure to obtain a solid, adding 10mL of methanol for dissolution, and adding sodium borohydride (20.0 mmol) at 0 ℃. After 1 hour, the reaction was quenched by addition of 2mL of acetone, diluted with 100mL of ethyl acetate, washed successively with saturated sodium bicarbonate (20 mL), 1N hydrochloric acid (20 mL), saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and filtered. After concentration, intermediate (3) was a white solid in 95% yield in step one.
Step two: the intermediate (3) is synthesized into the saxagliptin intermediate (1), and the specific operation is as follows:
the prepared intermediate (3) (38 mmol) is added into 40mL of methanol, stirred to be dissolved, then 4N HCl dioxane solution is added, stirred for 2 hours at normal temperature, cooled to 0 ℃ after the reaction is completed, 40% NaOH aqueous solution is added dropwise, and the pH value of the solution is regulated to 9-10. Then tert-butyl dicarbonate (45 mmol) was added, stirred at room temperature while 40% NaOH solution was added to keep the pH of the solution at 9-10, after the reaction was completed (TLC detection), part of the solvent was distilled off under reduced pressure, extracted with ethyl acetate (2X 40 mL), 30mL of ethyl acetate was added to the aqueous phase, and acidified to pH 2-3 with 3N hydrochloric acid under ice-bath cooling. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (2X 30 mL), the organic phases were combined, washed with saturated brine (2X 10 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a white solid product (1), purity: 99.6%, and the yield of the second step is 98%.
Example 2:
the embodiment discloses a preparation method of a saxagliptin intermediate (1), which comprises a first step and a second step, wherein the total reaction flow is as follows:
step one: after condensation of hydroxyadamantanone acetic acid with (S) -tert-butylsulfinamide, reduction yields chiral intermediate (3) as follows:
to a 25mL round bottom flask was added 10mL of dry dichloromethane, and (R) -tert-butylsulfinamide (5.0 mmol), hydroxyadamantanone-base acetic acid (6.0 mmol), tetraisopropyl titanyl (2.97 mL,10.0 mmol). Stirring at room temperature for 24 hours, adding 5mL of saturated salt water for quenching, filtering by diatomite, evaporating the solvent under reduced pressure to obtain a solid, adding 10mL of methanol for dissolution, and adding sodium borohydride (20.0 mmol) at 0 ℃. After 1 hour, the reaction was quenched by addition of 2mL of acetone, diluted with 100mL of ethyl acetate, washed successively with saturated sodium bicarbonate (20 mL), 1N hydrochloric acid (20 mL), saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and filtered. Concentrating. Intermediate (3) was obtained as a white solid in 96% yield in step one.
Step two: the intermediate (3) is synthesized into the saxagliptin intermediate (1), and the specific operation is as follows:
the intermediate (3) (38 mmol) was added to 40mL of methanol, and the mixture was stirred to dissolve the intermediate, followed by addition of 4N HThe dioxane solution of Cl is stirred for 2 hours at normal temperature, after the reaction is completed, the solution is cooled to 0 ℃, 40 percent of NaOH aqueous solution is dripped, and the pH value of the solution is regulated to 9-10. Then tert-butyl dicarbonate (45 mmol) was added, stirred at room temperature while 40% NaOH solution was added to keep the pH of the solution at 9-10, after the reaction was completed (TLC detection), part of the solvent was distilled off under reduced pressure, extracted with ethyl acetate (2X 40 mL), 30mL of ethyl acetate was added to the aqueous phase, and acidified to pH 2-3 with 3N hydrochloric acid under ice-bath cooling. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (2X 30 mL), the organic phases were combined, washed with saturated brine (2X 10 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the product (1) as a white solid in 96% yield in step two. m.p.177-179 ℃; the purity is 99.9 percent, t r=11.01 min [ HPLC normalization method: chromatographic column Chiralpak AD-H column (4.6 mm. Times.250 mm,5 μm), mobile phase V Isopropyl alcohol ∶V N-hexane =20: 80, detection wavelength 215nm, flow rate 1m L/min, column temperature 35 DEG C]。 1 H NMR(400MHz，CDCl 3 )δ:1.45(s，9H)，1.64，1.55(m，12H，2.05(m，2H)，3.5(brs，1H)，5.27(d，J＝8.8Hz，2H)。
The invention provides fig. 1, 2 and 3, wherein fig. 1 is a preparation process of a saxagliptin intermediate (1) in the invention, fig. 2 is an HPLC profile of the saxagliptin intermediate (1) prepared in example one, and fig. 3 is an HPLC profile of the saxagliptin intermediate (1) prepared in example two.
From the examples 1 and 2, the novel process adopted by the invention for synthesizing the saxagliptin intermediate (1) has the advantages of high acceptance, high purity, simple operation, less three wastes and easy industrial production.
The foregoing description is only of the preferred embodiments of the present application and is not intended to limit the present application.

Claims (1)

1. The preparation method of the saxagliptin intermediate is characterized in that the synthetic route of the saxagliptin intermediate is as follows:
；
the method comprises the following specific steps:
step one: mixing hydroxyadamantanone base acetic acid (2) with (S) -tert-butylsulfinamide by using methylene dichloride as a solvent, carrying out condensation reaction in the presence of tetraisopropyl titanyl, finishing the reaction after 24 hours at room temperature, adding reducing agent sodium borohydride, quenching after 1 hour of reduction, and carrying out extraction, drying and concentration operations to generate chiral intermediate (3) for the next reaction;
step two: dissolving the intermediate (3) in methanol, adding HCl dioxane solution with the concentration of 4mol/L, removing tert-butylsulfinyl protecting group, adjusting the pH to 9-12 with sodium hydroxide, and adding BOC anhydride to generate the saxagliptin intermediate (1).
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103965065A (en) * 2013-02-01 2014-08-06 上海现代制药股份有限公司 Saxagliptin intermediate, its salt, preparation method and application
CN104098487A (en) * 2014-07-31 2014-10-15 天津民祥生物医药科技有限公司 Method for preparing N-tert-butyloxycarbonyl-3-hydroxy-1-adamantyl-d-glycine
CN113527213A (en) * 2020-04-20 2021-10-22 上海英诺富成生物科技有限公司 Gonadotropin releasing hormone receptor antagonists and uses thereof
CN114621068A (en) * 2022-03-31 2022-06-14 沧州那瑞化学科技有限公司 Preparation method of 3-hydroxy-1-adamantane methyl ketone and method for synthesizing saxagliptin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103965065A (en) * 2013-02-01 2014-08-06 上海现代制药股份有限公司 Saxagliptin intermediate, its salt, preparation method and application
CN104098487A (en) * 2014-07-31 2014-10-15 天津民祥生物医药科技有限公司 Method for preparing N-tert-butyloxycarbonyl-3-hydroxy-1-adamantyl-d-glycine
CN113527213A (en) * 2020-04-20 2021-10-22 上海英诺富成生物科技有限公司 Gonadotropin releasing hormone receptor antagonists and uses thereof
CN114621068A (en) * 2022-03-31 2022-06-14 沧州那瑞化学科技有限公司 Preparation method of 3-hydroxy-1-adamantane methyl ketone and method for synthesizing saxagliptin

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Pd(OAc)2-Catalyzed Asymmetric Hydrogenation of α-Iminoesters;Jianzhong Chen et al.;《Org. Lett.》;20191101;第21卷(第22期);第9060–9065页 *

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