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Preparation methods of SGLT-2 diabetes inhibitors and intermediates thereof

A technology of SGLT-2, 1. SGLT-2 is applied in the field of preparation of SGLT-2 inhibitors, which can solve the problems of high route cost, extremely high reaction temperature, high moisture requirements, and difficult operation.

Active Publication Date: 2017-09-15
山东科巢生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This route improves the docking reaction between the key intermediate and gluconolactone, and obtains the pivalate derivative of dapagliflozin in one step, which greatly shortens the experimental steps, but needs to use anhydrous zinc bromide to exchange Grignard reagent, The requirements for reaction temperature and moisture are extremely high, the scale-up operation of the process is difficult, and the cost of the route is still high, so it is still necessary to find a method with a simple process route, low cost, and suitable for industrial production to synthesize dapagliflozin and empagliflozin

Method used

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  • Preparation methods of SGLT-2 diabetes inhibitors and intermediates thereof
  • Preparation methods of SGLT-2 diabetes inhibitors and intermediates thereof
  • Preparation methods of SGLT-2 diabetes inhibitors and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] (5-Bromo-2-chlorophenyl)(4-ethoxyphenyl)methanol

[0058]

[0059] Add (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone 1a (33.96g, 100mmol), tetrahydrofuran (170mL), methanol (34mL) into the three-necked flask, stir well and cool to 0~ At 5°C, sodium borohydride (4.54 g, 120 mmol) was added in batches, and after the addition was completed, the temperature was slowly raised to room temperature for 1-2 hours. After the reaction is completed, cool to 0-5°C and add 0.5mol / L dilute hydrochloric acid (170mL) to quench the reaction, add ethyl acetate (170mL) to the aqueous phase to extract twice, combine the organic phases, wash once with saturated brine (170mL), and dry over sodium sulfate , after concentrating, beat with ethyl acetate petroleum ether, filter, wash with a small amount of petroleum ether, and dry to obtain compound (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanol 2a (31.43g, 92%) .

[0060] Here the reducing agent sodium borohydride can be replaced by b...

Embodiment 2

[0062] (5-iodo-2-chlorophenyl)(4-ethoxyphenyl)methanol

[0063]

[0064] Add (5-iodo-2-chlorophenyl)(4-ethoxyphenyl)methanone 1b (38.66g, 100mmol), tetrahydrofuran (193mL), methanol (39mL) into the three-necked flask, stir well and cool to 0~ At 5°C, potassium borohydride (6.47 g, 120 mmol) was added in batches, and after the addition was completed, the temperature was slowly raised to room temperature for 2-3 hours. After the reaction is completed, cool to 0-5°C and add 0.5mol / L dilute hydrochloric acid (193mL) to quench the reaction, add ethyl acetate (193mL) to the aqueous phase to extract twice, combine the organic phases, wash once with saturated brine (193mL), and dry over sodium sulfate , concentrated with ethyl acetate petroleum ether, filtered, washed with a small amount of petroleum ether, and dried to obtain compound (5-iodo-2-chlorophenyl)(4-ethoxyphenyl)methanol 2b (34.98g, 90%) .

Embodiment 3

[0066] 4-Bromo-1-chloro-2-((4-ethoxyphenyl)(methoxy)methyl)benzene

[0067]

[0068] Add 2a (34.16 g, 100 mmol), toluene (170 mL) and 15% methanolic hydrochloric acid solution (102 mL) into a three-necked flask, stir well and heat to 65-70° C. to react overnight. After the reaction was completed, cool to room temperature, add water (170mL) to separate the liquids, extract the water phase with toluene (170mL) once more, combine the organic phases and wash with saturated brine once (170mL), dry over sodium sulfate, filter, concentrate and wash with ethyl acetate The compound 4-bromo-1-chloro-2-((4-ethoxyphenyl)(methoxy)methyl)benzene 4a (32.72 g, 92%) was obtained by recrystallization from petroleum ether mixed solvent.

[0069] MS(ESI)m / z=355.1[M+H] + , 1 HNMR (CDCl3, 400MHz) δ7.80(d, J=2.4Hz, 1H), 7.35-7.25(m, 3H), 7.19(d, J=8.5Hz, 1H), 6.90-6.85(m, 2H), 5.66(s,1H),4.03(q,J=6.9Hz,2H),3.40(s,3H),1.29(t,J=6.8Hz,3H).

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Abstract

The invention provides a preparation method of an intermediate compound 7 of an SGLT-2 diabetes inhibitor dapagliflozin and an intermediate compound 8 of a SGLT-2 diabetes inhibitor empagliflozin, and new synthesis method of two final products. The preparation method comprises the following steps: carrying out carbonyl group reduction and hydroxyl group protection on a (5-halo-2-chlorophenyl)(4-ethoxyphenyl)ketone compound 1 used as an initial raw material to obtain a Grignard addition reaction key compound 4, and carrying out Grignard addition and acetylation to obtain the compound 7 and the compound 8. The dapagliflozin and the empagliflozin are respectively prepared from the compound 8. The methods have the advantages of simplicity in operation, high yield, high purity of the obtained products, and suitableness for amplified production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a new method for preparing SGLT-2 inhibitors. Specifically, the invention discloses a preparation method for SGLT-2 inhibitor dapagliflozin, empagliflozin and their common intermediates, which are used for treating diabetes. Background technique [0002] SGLT-2 inhibitors are a class of non-insulin-dependent oral drugs, which can selectively inhibit the reabsorption of filtered glucose by the proximal tubules of the glomerulus, excrete excess glucose from the urine, directly reduce blood sugar and are not easy to induce Hypoglycemia, used to treat hyperglycemia in type 2 diabetes. In 2014, the United States approved the SGLT-2 inhibitor hypoglycemic drug Dapagliflozin developed by AstraZeneca. Empagliflozin, which has a similar structure, has shown significant curative effect, good safety and tolerability. It has also been approved for marketing and has broad market ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/04C07H1/00C07D309/10C07D407/12
CPCC07D309/10C07D407/12C07H1/00C07H15/04
Inventor 郑旭春张一平吴怡华
Owner 山东科巢生物制药有限公司
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