A kind of preparation method of granisetron intermediate

A technology of intermediates and schemes, applied in the field of preparation of granisetron intermediates, can solve the problems of high cost, low product purity and yield, and high equipment and operational requirements

Active Publication Date: 2020-10-20
杭州励德生物科技有限公司
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] U.S. Patent No. 4,705,858A reports in detail the synthetic method of this intermediate and the synthetic method of isomers, but adopts relatively expensive reagent Pt, and dangerous higher LiAlH4 and high-pressure hydrogenation and other reaction conditions, which are harmful to equipment and operation more demanding
[0007] CN1451660A discloses a preparation method of granisetron, wherein step e discloses the method of obtaining 3α-homotropinamine by catalytic hydrogenation reduction of 3-homotropinone oxime, and the 3α-homotropinamine obtained by this method has been verified. Tropicanamine is actually a mixture containing isomers. When it is directly used for the synthesis of granisetron, since the mixture contains a large amount of isomer impurities, the purity and yield of the synthesized granisetron target product are low. lower

Method used

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  • A kind of preparation method of granisetron intermediate
  • A kind of preparation method of granisetron intermediate
  • A kind of preparation method of granisetron intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] 1. Synthesis of Pseugranicine (Ⅳ)

[0042] Add 0.44kg Na in 3L water 2 HPO 4 And 0.09kg of methylamine hydrochloride, add 0.2kg of acetone dicarboxylic acid, cool to about 0°C, add 0.25kg of glutaraldehyde dropwise, keep at 0°C and stir for 1h, warm up to 25°C and stir for 24h. Adjust the pH to about 3 with 0.2L concentrated hydrochloric acid (concentration 36%), raise the temperature to 75° C. and stir for 1 hour, cool to room temperature, and adjust the pH to above 10 with a 50% NaOH solution. After extraction with DCM, the solvent was spun off to obtain a crude product. Add 0.4kg of neutral alumina with 0.2L methyl tert-butyl ether under stirring, heat to reflux, drop the crude product, stir and reflux for 0.5h, naturally cool to room temperature, filter, and use petroleum ether: methyl tert-butyl ether = The filter cake was rinsed three times with 3:1 solvent. The filtrate was spin-dried to obtain 0.16 kg pseudopusicine (IV).

[0043] 2. Synthesis of 3-Homotropine oxi...

Embodiment 2

[0049] Steps 1-2 are the same as in Example 1, the difference is:

[0050] 3. Synthesis of 3α-High Tropine Amine (Ⅰ)

[0051] Add 445ml of 70% Red-Al to 320ml of THF, add 306.8g of titanium tetrachloride dropwise, control the temperature within 0±5℃, stir for 2h, add dropwise 136g of 3-high tropinone oxime, control the temperature at 0±5℃, after dripping, warm to room temperature and react for 8h. Add 20% NaOH aqueous solution, separate the layers, wash the organic phase with saturated ammonium chloride and saturated sodium chloride, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and collect the residue by distillation under reduced pressure 92~96 At a temperature of 10 mmHg, 81.5 g of 3α-homotropane (I) was obtained. Purity 89.9%, yield: 65.4%.

[0052] 1 H NMR(400MHz, CDCl 3 )δ3.2(m,1H),3.0(d,J=6.0Hz,2H), 2.45(s,3H), 2.29(m,2H), 1.94(m,3H), 1.79(br,6H), 1.46 (m, 1H), 1.13 (m, 2H), 0.98 (m, 2H).

Embodiment 3

[0054] Steps 1-2 are the same as in Example 1, the difference is:

[0055] 3. Synthesis of 3α-High Tropine Amine (Ⅰ)

[0056] Add 500ml of 70% Red-Al to 320ml of THF, add 89.2g of concentrated sulfuric acid (98%) dropwise, control the temperature within 0±5℃, stir for 2h, add dropwise 152g of 3-hotropine oxime, control The temperature is at 0±5°C, after the addition is completed, the temperature is raised to room temperature and reacted for 8 hours. Add 20% NaOH aqueous solution, separate the layers, wash the organic phase with saturated ammonium chloride and saturated sodium chloride, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and collect the residue by distillation under reduced pressure 92~96 At a temperature of 10mmHg, 104.9 g of 3α-homotropane (I) was obtained. Purity 90.5%, yield: 75.3%.

[0057] 1 H NMR(400MHz, CDCl 3 )δ3.2(m,1H),3.0(d,J=6.0Hz,2H), 2.45(s,3H), 2.29(m,2H), 1.94(m,3H), 1.79(br,6H), 1.46 (m, 1H),...

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Abstract

The invention discloses a preparation method of a granisetron intermediate. The preparation method comprises the following steps: step 1, carrying out a Mannich reaction on acetone dicarboxylic acid represented by a formula III to obtain pseudopelletierine represented by a formula IV; step 2, carrying out a reaction on the pseudopelletierine and hydroxylamine to prepare 3-pseudopelletierine oximerepresented by a formula V; and step 3, carrying out preparation by adopting one of the following schemes: (1) carrying out catalytic reduction on the 3-pseudopelletierine oxime through sodium bis(2-methoxyethoxy)aluminumhydride and Lewis acid to obtain a crude product of endo-3-amine-9-methyl-9-azabicyclo[3,3,1]nonane represented by a formula I, and directly using the crude product of endo-3-amine-9-methyl-9-azabicyclo[3,3,1]nonane to prepare granisetron, or purifying the crude product of endo-3-amine-9-methyl-9-azabicyclo[3,3,1]nonane for preparing granisetron; and (2) carrying out catalytichydrogenation reduction on the 3-pseudopelletierine oxime through Raney nickel to obtain a mixture of endo-3-amine-9-methyl-9-azabicyclo[3,3,1]nonane, purifying the mixture to obtain endo-3-amine-9-methyl-9-azabicyclo[3,3,1]nonane represented by the formula I, and using the endo-3-amine-9-methyl-9-azabicyclo[3,3,1]nonane used for preparing granisetron. The method has the advantages of mild reaction conditions, high reaction yield and low cost, and is suitable for industrial production.

Description

Technical field [0001] The invention relates to the technical field of production of pharmaceutical intermediates, in particular to a preparation method of granisetron intermediates. Background technique [0002] Granisetron is a potent and highly selective 5-HT3 receptor antagonist in the peripheral and central nervous system. It directly acts on the central chemoreceptive area and the 5-HT3 receptors in the peripheral vagus nerve endings, inhibiting nausea and vomiting. It has a good preventive effect on nausea and vomiting caused by radiotherapy, chemotherapy and surgery. In December 1993, it was approved by the FDA for listing in the United States. After Roche took over granisetron in 2000, after clinical research, Roche applied for a new indication. In August 2002, it was approved by the US FDA. The injection was used to treat nausea and vomiting after surgery. At present, granisetron hydrochloride injections and oral tablets have been marketed in more than a dozen countri...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D451/14
CPCC07D451/14
Inventor 林浩李彬任国宝吴彦
Owner 杭州励德生物科技有限公司
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