CN105061428B - Method for refining tadalafil - Google Patents

Method for refining tadalafil Download PDF

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Publication number
CN105061428B
CN105061428B CN201510529107.XA CN201510529107A CN105061428B CN 105061428 B CN105061428 B CN 105061428B CN 201510529107 A CN201510529107 A CN 201510529107A CN 105061428 B CN105061428 B CN 105061428B
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tadalafil
hplc
refining
crude
value
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CN105061428A (en
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金从阳
刘洋
张文灵
王鹏
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Zhejiang Huahai Pharmaceutical Co Ltd
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Zhejiang Huahai Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention realizes the recrystallization of tadalafil by using a method of adjusting the pH by using cheap hydrochloric acid and ammonia water. The process provided by the invention has the advantages of reducing the using amount of the solvent, reducing the drying temperature, being beneficial to increasing the productivity and improving the economic benefit.

Description

Method for refining tadalafil
Technical Field
The invention relates to a method for refining tadalafil.
Background
Tadalafil is chemically (6R, 12aR) -6- (1, 3-benzodioxol-5-yl) -2-methyl-2, 3, 6, 7, 12, 12 a-hexahydropyrazino [1 ', 2', 1, 6] pyrido [3, 4-b ] indole-1, 4-dione, having the following structural formula:
tadalafil structural formula
Tadalafil, a second generation phosphodiesterase type 5 inhibitor (PDE 5 inhibitor), was developed by american gifts and mainly treats male sexual dysfunction by increasing intracellular concentration of cyclic guanosine monophosphate (cGMP) through inhibition of cGMP degrading cGMP type 5 phosphodiesterase activity, resulting in relaxation of smooth muscle, increased arterial blood flow in the corpus cavernosum of the penis, and erection. From the currently searched synthetic routes of tadalafil, the synthetic route using D-tryptophan and piperonal as key materials has the advantages of simple reaction, high yield, low toxicity of raw materials, and the like, and is widely used (refer to patents: WO2004011463, US7550479, and EP1546149B 1).
Crude tadalafil prepared by WO2004011463 has some impurities, typically the highest content of impurity a (diastereomer), the structure of impurity a being shown below:
structure of impurity A
The method for refining tadalafil in the patent is as follows: at 80oTadalafil was dissolved in 13 times the mass of acetic acid (HOAc) at C, the solution was concentrated to one third of the original volume, and then cooled to room temperature. The crystals were filtered, washed with methyl tert-butyl ether (MTBE) and purified at 80 deg.CoAnd C, vacuum drying. The refining method has the defects of large solvent consumption, high drying temperature of acetic acid, easy residue and the like, and the production cost is high.
WO2006049986A1 discloses that a solvent for preparing tadalafil crystal form I comprises ketone and C3-C7Ester, DMF, DMSO, ethanol, acetonitrile, chlorohydrocarbon, tert-butanol, ethyl acetate, DMA, dioxane, and N-methyl pyrrole. From the viewpoint of environmental protection and economic cost, ketones, esters, alcoholsThe solvent-like solvent is an ideal solvent for preparing the tadalafil crystal form I, but the volume of the solvent is larger than the mass of the tadalafil, and is about 55-200 mL/g.
Disclosure of Invention
The invention provides a method for refining tadalafil, which comprises the following steps:
(1) dispersing the crude tadalafil product into a specific organic solvent, dropwise adding hydrochloric acid to adjust the pH value to enable the crude product to be clear, and filtering;
(2) ammonia water is dripped to adjust the pH value to gradually separate out crystals, and the crystals are further cooled and crystallized;
(3) filtering, washing and drying.
The organic solvent in the step (1) is methanol or ethanol, preferably methanol.
The dosage of the organic solvent in the step (1) is 5 ~ 10 times, preferably 7 times of the mass of the crude tadalafil product.
The hydrochloric acid in the step (1) is preferably refined hydrochloric acid.
Step (1) preferably adjusts the pH to 1 ~ 3, preferably 3.
The ammonia water in the step (2) is preferably strong ammonia water.
Step (2) preferably adjusts the pH to 4 ~ 7, preferably 5.
The pH value adjusting processes of the steps (1) and (2) are carried out at room temperature.
The cooling crystallization condition in the step (2) is preferably 0oAnd C, crystallizing for 1 hour.
The washing solvent in step (3) is preferably the same as in step (1).
The drying condition in the step (3) is preferably 70 times of normal pressureoAnd C, drying for 12 hours by hot air.
The invention realizes the purpose of purifying tadalafil by using a method of adjusting pH by using cheap hydrochloric acid and ammonia water, has simple operation, effectively reduces the using amount of a solvent, reduces the drying temperature, and has obvious economic benefit and environmental protection benefit.
Detailed Description
The following examples illustrate the present technology, but the present invention is not limited thereto:
reference example 1: preparation of crude tadalafil
With reference to patent WO2004011463, crude tadalafil was prepared in 58.3% overall yield, purity (HPLC): 99.30%, impurity a (hplc): 0.29%, other max monohetero (HPLC): 0.18 percent.
Example 1
20g of crude tadalafil prepared in reference example 1 was taken at room temperature and charged into a 500mL four-necked flask. 100g of methanol was added and the stirring was started. Slowly dripping refined hydrochloric acid into the bottle, adjusting the pH value of the system to 3, and gradually dissolving and cleaning the materials. Filtering, slowly dripping concentrated ammonia water into the bottle, adjusting the pH value of the system to 4, and gradually separating out crystals. Slowly cooling to 0oC is crystallized for 1 hour, filtered, washed by about 5g of methanol and at normal pressure of 70oC, drying for 12 hours by hot air to obtain 18.7g of tadalafil, the yield is 93.5%, and the purity (HPLC): 99.82%, impurity a (hplc): 0.09%, other max monohetero (HPLC): 0.10 percent.
Example 2
20g of crude tadalafil prepared in reference example 1 was taken at room temperature and charged into a 500mL four-necked flask. 100g of ethanol was added, and the stirring was started. Slowly dripping refined hydrochloric acid into the bottle, adjusting the pH value of the system to 3, gradually dissolving the materials, and filtering. Slowly dripping strong ammonia water into the bottle, adjusting the pH value of the system to 4, and gradually separating out crystals. Slowly cooling to 0oC is crystallized for 1 hour, filtered, washed by about 5g of ethanol and subjected to normal pressure of 70oC, drying for 12 hours by hot air to obtain 18.9g of tadalafil, wherein the yield is 94.5%, and the purity (HPLC): 99.70%, impurity a (hplc): 0.14%, other max monohetero (HPLC): 0.17 percent.
Example 3
20g of crude tadalafil prepared in reference example 1 was taken at room temperature and charged into a 500mL four-necked flask. Then, 140g of methanol was added, and the stirring was started. Slowly dripping refined hydrochloric acid into the bottle, adjusting the pH value of the system to 3, gradually dissolving the materials, and filtering. Slowly dripping strong ammonia water into the bottle, adjusting the pH value of the system to 4, and gradually separating out crystals. Slowly cooling to 0oC is crystallized for 1 hour, filtered, washed by about 5g of methanol and at normal pressure of 70oC heatAir-dried for 12 hours to obtain 18.6g of tadalafil, the yield is 93.0%, and the purity (HPLC): 99.99%, impurity a (hplc): n.d, other max monohetero (HPLC): 0.01 percent.
Example 4
20g of crude tadalafil prepared in reference example 1 was taken at room temperature and charged into a 500mL four-necked flask. 200g of methanol were added and the stirring was started. Slowly dripping refined hydrochloric acid into the bottle, adjusting the pH value of the system to 3, gradually dissolving the materials, and filtering. Slowly dripping strong ammonia water into the bottle, adjusting the pH value of the system to 4, and gradually separating out crystals. Slowly cooling to 0oC is crystallized for 1 hour, filtered, washed by about 5g of methanol and at normal pressure of 70oC, drying for 12 hours by hot air to obtain 17.8g of tadalafil, wherein the yield is 89.0 percent, and the purity (HPLC): 99.99%, impurity a (hplc): n.d, other max monohetero (HPLC): 0.01 percent.
Example 5
20g of crude tadalafil prepared in reference example 1 was taken at room temperature and charged into a 500mL four-necked flask. Then, 140g of methanol was added, and the stirring was started. Slowly dripping refined hydrochloric acid into the bottle, adjusting the pH value of the system to 2, gradually dissolving the materials, and filtering. Slowly dripping strong ammonia water into the bottle, adjusting the pH value of the system to 4, and gradually separating out crystals. Slowly cooling to 0oC is crystallized for 1 hour, filtered, washed by about 5g of methanol and at normal pressure of 70oC, drying for 12 hours by hot air to obtain 18.6g of tadalafil, the yield is 93.0%, and the purity (HPLC): 99.98%, impurity a (hplc): n.d, other max monohetero (HPLC): 0.01 percent.
Example 6
20g of crude tadalafil prepared in reference example 1 was taken at room temperature and charged into a 500mL four-necked flask. Then, 140g of methanol was added, and the stirring was started. Slowly dripping refined hydrochloric acid into the bottle, adjusting the pH value of the system to 1, gradually dissolving the materials, and filtering. Slowly dripping strong ammonia water into the bottle, adjusting the pH value of the system to 4, and gradually separating out crystals. Slowly cooling to 0oC is crystallized for 1 hour, filtered, washed by about 5g of methanol and at normal pressure of 70oC, drying for 12 hours by hot air to obtain 18.5g of tadalafil, wherein the yield is 92.5 percent, and the purity (HPLC): 99.98%, impurity a (hplc): n.d, other max monohetero (HPLC): 0.01 percent.
Example 7
20g of crude tadalafil prepared in reference example 1 was taken at room temperature and charged into a 500mL four-necked flask. Then, 140g of methanol was added, and the stirring was started. Slowly dripping refined hydrochloric acid into the bottle, adjusting the pH value of the system to 3, gradually dissolving the materials, and filtering. Slowly dripping strong ammonia water into the bottle, adjusting the pH value of the system to 5, and gradually separating out crystals. Slowly cooling to 0oC is crystallized for 1 hour, filtered, washed by about 5g of methanol and at normal pressure of 70oC, drying for 12 hours by hot air to obtain 19.2g of tadalafil, wherein the yield is 96.0 percent, and the purity (HPLC): 99.99%, impurity a (hplc): n.d, other max monohetero (HPLC): 0.01 percent.
Example 8
20g of crude tadalafil prepared in reference example 1 was taken at room temperature and charged into a 500mL four-necked flask. Then, 140g of methanol was added, and the stirring was started. Slowly dripping refined hydrochloric acid into the bottle, adjusting the pH value of the system to 3, gradually dissolving the materials, and filtering. Slowly dripping strong ammonia water into the bottle, adjusting the pH value of the system to 6, and gradually separating out crystals. Slowly cooling to 0oC is crystallized for 1 hour, filtered, washed by about 5g of methanol and at normal pressure of 70oC, drying for 12 hours by hot air to obtain 19.4g of tadalafil, wherein the yield is 97.0 percent, and the purity (HPLC): 99.81%, impurity a (hplc): 0.15%, other max monohetero (HPLC): 0.02 percent.
Example 9
20g of crude tadalafil prepared in reference example 1 was taken at room temperature and charged into a 500mL four-necked flask. Then, 140g of methanol was added, and the stirring was started. Slowly dripping refined hydrochloric acid into the bottle, adjusting the pH value of the system to 3, gradually dissolving the materials, and filtering. Slowly dripping strong ammonia water into the bottle, adjusting the pH value of the system to 7, and gradually separating out crystals. Slowly cooling to 0oC is crystallized for 1 hour, filtered, washed by about 5g of methanol and at normal pressure of 70oC, drying for 12 hours by hot air to obtain 19.5g of tadalafil, wherein the yield is 97.5 percent, and the purity (HPLC): 99.64%, impurity a (hplc): 0.23%, other max monohetero (HPLC): 0.05 percent.

Claims (7)

1. A method of refining tadalafil, comprising the steps of:
(1) dispersing the crude tadalafil product into methanol, dropwise adding hydrochloric acid to adjust the pH value to 1-3 to enable the crude product to be clear, and filtering;
(2) dropwise adding ammonia water to adjust the pH value to 4-5 so as to gradually separate out crystals, and further cooling and crystallizing;
(3) filtering, washing and drying.
2. The method for refining tadalafil according to claim 1, wherein the amount of the organic solvent used in step (1) is 5 to 10 times the mass of the crude tadalafil.
3. The method for refining tadalafil according to claim 2, wherein the amount of the organic solvent used in step (1) is 7 times the amount of the crude tadalafil.
4. A process for refining tadalafil according to claim 1, characterized in that said adjusting of said pH to 3 in step (1).
5. The method for purifying tadalafil according to claim 1, wherein said hydrochloric acid of step (1) is purified hydrochloric acid.
6. A process for refining tadalafil according to claim 1, characterized in that step (2) adjusts the pH to 5.
7. The method according to claim 1, wherein the aqueous ammonia used in the step (2) is concentrated aqueous ammonia.
CN201510529107.XA 2015-08-26 2015-08-26 Method for refining tadalafil Active CN105061428B (en)

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Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105272981A (en) * 2015-11-19 2016-01-27 中国药科大学 New Tadalafil crystal form
CN106674223A (en) * 2016-06-29 2017-05-17 浙江华海药业股份有限公司 Method for refining tadalafil
CN114702493B (en) * 2022-06-07 2022-08-26 南京正科医药股份有限公司 Refining method of Tadalafil crystal form I

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1671706A (en) * 2002-07-31 2005-09-21 利利艾科斯有限公司 Modified pictet-spengler reaction and products prepared therefrom
WO2006049986A1 (en) * 2004-10-28 2006-05-11 Dr. Reddy's Laboratories Ltd. Polymorphic forms of tadalafil
CN102367253A (en) * 2011-09-20 2012-03-07 浙江华海药业股份有限公司 Method for preparing Tadalafil crystal form A

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1671706A (en) * 2002-07-31 2005-09-21 利利艾科斯有限公司 Modified pictet-spengler reaction and products prepared therefrom
WO2006049986A1 (en) * 2004-10-28 2006-05-11 Dr. Reddy's Laboratories Ltd. Polymorphic forms of tadalafil
CN102367253A (en) * 2011-09-20 2012-03-07 浙江华海药业股份有限公司 Method for preparing Tadalafil crystal form A

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