CN1362400A - Synthesis of terbinafine hydrochloride - Google Patents

Abstract

The invention provides a method for synthesizing Terbinafine Hydrochloride. Using tert-butylacetylene as raw material, convert it into 3,3-dimethyl-1-butynyllithium or 3,3-dimethyl-1-butynyl Grignard reagent, and then synthesize the intermediate 1-halo- 6,6-Dimethyl-2-hepten-4-yne; the above-mentioned intermediates 1-halo-6,6-dimethyl-2-hepten-4-yne and N-methyl-1-naphthyne After the amine is heated and condensed in an alkaline system, it is salified with HCl to obtain the product terbinafine hydrochloride. The reaction of the invention is easy to control and simple, the raw materials are easy to obtain, and the operation is convenient. During the synthesis process, the intermediate operation link was reduced, and the yield was improved.

Description

Synthesis of Terbinafine Hydrochloride

technical field

The invention relates to a synthetic route of Terbinafine Hydrochloride.

Background technique

特比萘芬的合成路线有多种：①W.Granitzer等(Tetra.Lett.1979，34，3145.)在甲苯溶液中，用Dibal(diisobutylaluminum hydride)可以选择性的将二炔化合物还原为trans-式烯炔，反应式如下：

②在甲醛和硼氢化钠存在下，A.Stutz(Canadian Patent 1157023)将萘胺和trans-6，6-二甲基庚-2-烯-4-炔-1-醛还原胺化可以得到Terbinafine，反应式如下：

As an allylamine antifungal drug, terbinafine hydrochloride can effectively inhibit squalene cyclooxygenase, and in the process of fungal reproduction, the biosynthesis of ergosterol requires squalene The role of cyclooxygenase, so inhibition of squalene cyclooxygenase can effectively kill fungi, thereby curing diseases caused by fungal infections. Therefore terbinafine hydrochloride has larger market demand, and its molecular formula is:

The synthetic route of terbinafine has multiple: 1.W.Granitzer etc. (Tetra.Lett.1979,34,3145.) in toluene solution, diyne compound can be selectively reduced to trans- Formula enyne, the reaction formula is as follows:

② In the presence of formaldehyde and sodium borohydride, A.Stutz (Canadian Patent 1157023) reductively aminated naphthylamine and trans-6,6-dimethylhept-2-en-4-yne-1-aldehyde to obtain Terbinafine , the reaction formula is as follows:

③K.Karimian et al. (US Patent 5817875) used N-methyl-1-naphthylmethylamine hydrochloride as the starting material, and obtained Terbinafine through the formation of intermediate 2,3-epoxypropane, addition reaction and dehydration, and the reaction The formula is as follows:

(4) K. Karimian et al. (US Patent 5817875) also reported the application of Wittig reaction to synthesize Terbinafine, the reaction formula is as follows:

⑤ In the presence of a palladium catalyst, Gotteland et al. (SYNLETT, 1995, 931. Tetra. Lett. 1996, 37 (1), 57.) can stereoselectively couple vinyl chlorides with terminal alkynes, high yield Synthesis of Terbinafine, the reaction scheme is as follows:

The above routes either have low yields, rare raw materials, or difficult preparation of intermediates, or expensive catalysts that are not suitable for industrialized production.

Contents of the invention

The problem to be solved by the present invention is to provide a method for efficiently and conveniently synthesizing the intermediate 1-halo-6,6-dimethyl-2-hepten-4-yne, and then preparing terbinafine hydrochloride.

The present invention uses tert-butylacetylene as a raw material, converts it into 3,3-dimethyl-1-butynyl lithium or 3,3-dimethyl-1-butynyl Grignard reagent, and then synthesizes the intermediate 1- Halo-6,6-dimethyl-2-hepten-4-yne; the above intermediate 1-halo-6,6-dimethyl-2-hepten-4-yne and N-methyl-1- After the naphthylmethylamine is heated and condensed in an alkaline system, it is salified with HCl to obtain the product terbinafine hydrochloride.

The reaction formula is described as follows:

Main reaction steps of the present invention are as follows:

1) Synthesis of 1-halo-6,6-dimethyl-2-hepten-4-yne:

At -10-60°C, in an organic solvent, using tert-butylacetylene as a raw material, the molar ratio with alkyl Grignard (R-MgX) reagent or lithium reagent (RLi) is 1:0.5-3, recommended as 1: 0.8～1.5, reacted for 0.5～36 hours, converted into 3,3-dimethyl-1-butynyl lithium or 3,3-dimethyl-1-butynyl Grignard reagent, the R C ₁ ~ C ₁₀ straight chain or branched hydrocarbon groups, such as: methyl, vinyl, n/isopropyl, n/tert-butyl, n-hexyl, etc., the X is a halogen atom such as Cl and Br wait. The R group in lithium reagent (RLi) recommends n-butyl and other alkyl groups;

At -20 to 40°C, in an organic solvent, the above reaction product is reacted with acrolein for 1 to 30 hours to generate 6,6-dimethyl-1-heptene-4-yn-3-ol, of which acrolein The molar ratio of the amount used is 0.5 to 5 times that of tert-butylacetylene, and it is recommended to be 0.8 to 1.5 times;

Under the catalysis _{of ZnCl2} , at -20℃～reflux temperature, in an organic solvent, use a halogenation reagent for halogenation and rearrangement. The molar ratio of the halogenation reagent is 1 to 6 times that of tert-butylacetylene, and it is recommended to be 1:1 to 2.4 times , reacted for 0.5 to 30 hours to obtain 1-halo-6,6-dimethyl-2-hepten-4-yne, and the halogen atoms are Cl, Br and the like. The molar ratio of catalyst ZnCl ₂ is 0.2-4 times that of tert-butyl acetylene, and the halogenation reagent is PCl ₅ , POCl ₃ , PBr ₃ /HBr, thionyl chloride or sulfone dichloride.

2) synthetic terbinafine hydrochloride:

N-alkyl-1-naphthylmethylamine and 1-halo-6,6-dimethyl-2-hepten-4-yne are condensed at 10-140°C by the action of a base in an organic solvent, and then In the alcohol system, HCl is used to form a salt to obtain the product terbinafine hydrochloride, and finally a qualified product meeting the requirements is obtained by recrystallization, and the content is >99% (HPLC). The base is such as Na ₂ CO ₃ , NaHCO ₃ , K ₂ CO ₃ or KHCO ₃ and an organic base such as pyridine, triethylamine or tributylamine. The alcohol is C ₁ -C ₁₀ straight chain or branched chain alcohol, for example: methanol, ethanol, isopropanol and the like.

Prolonging the reaction time in the above reaction is beneficial to the reaction. Described organic solvent is the alcohol of toluene, benzene, low carbon chain, ether, cyclohexane, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), carbon tetrachloride, dichloromethane, petroleum Ether, acetone, chloroform, n-hexane, n-heptane or dioxane, etc. In the above-mentioned reaction process, the intermediate can be purified as much as possible without purification.

The remarkable advantage of the present invention is: in synthesizing 1-halo-6,6-dimethyl-2-hepten-4-yne, overcome the problem of high cost, the safety of operation and the limitation that industry has, and Reduced loss and increased yield. In addition, if the intermediate product 6 is not purified in the reaction process, the 6-dimethyl-1-hepten-4-yn-3-alcohol is beneficial to the reaction and operation. In the halogenation rearrangement reaction, we use _ZnCl as a catalyst, The ratio of forward and reverse products in the reactant can reach about 1:7, and the content of the trans product can be obtained by rectification>95%, and the total yield can reach more than 60%.

In the synthesis of Terbinafine hydrochloride, the yield of this step can reach more than 90%.

By adopting the method of the invention to synthesize terbinafine hydrochloride, the reaction is easy to control and relatively simple, the raw materials are easy to obtain, and the operation is convenient. In the synthesis process, under the situation that the yield is not affected as much as possible, the intermediate can be purified as much as possible without purification, which reduces the intermediate operation links, and the results show that the yield has been improved, so the method of the present invention is a suitable industrial method. method of production.

Detailed ways

The following examples will help to understand the present invention, but can not limit the content of the present invention.

Embodiment 1

1. 1-bromo-6,6-dimethyl-2-hepten-4-yne

1000ml reaction bottle, under _N2 protection, add 150mlTHF, 24.8g tert-butylacetylene. After cooling, 180 ml (2.0 M) of butyllithium cyclohexane solution was added dropwise. After the dropwise addition, the mixture was kept warm for 2 hours, and then heated to a weak reflux state for reaction for 4 hours. Cool to -10～0℃.

Add a mixed solution of 17.9 g of acrolein and 100 ml of THF, and react at room temperature for 3 to 5 hours. Cool the reaction solution and adjust the pH value to 5-6. The reaction solution is separated into layers, the organic phase is separated, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined. It was washed with saturated NaCl aqueous solution, dried and concentrated to obtain 66.6 g (GC content: 51.5%).

Add 10 g of anhydrous zinc chloride to a 3000 ml reaction flask, add 165 g of PBr ₃ under the protection of N ₂ , and heat to 80-90° C. for 0.5 hour. After cooling, add 1000ml cyclohexane and 500ml THF, add the mixture of 66.6g concentrated solution and 200ml cyclohexane obtained above at 0-5°C, and react at room temperature for 5 hours.

Cool the reaction solution, pour it into ice water, separate the organic phase, extract the water phase with 1,2-dichloroethane, wash the combined organic phase with saturated NaCl solution, dry, and concentrate to obtain 104 g of brown liquid, GC content: 33.4 % (trans), 6.37% (cis), trans/cis=5.24:1.

Rectification: 36.5g light yellow liquid, GC content: 90.15% (trans), 2.75% (cis).

Bp: 51-55℃/1～2mmHg

Theoretical yield: 60.3g,

Actual yield: 36.5 g.

Actual yield: 60.5%

Example 2

1. 1-Chloro-6,6-dimethyl-2-heptene-4-yne

1000ml reaction bottle, under _N2 protection, add 150mlTHF, 24.8g tert-butylacetylene. Add 245ml (1.43M) of THF solution of ethylmagnesium bromide, heat up to weak reflux and react for 4 hours. Cool to -10～0℃.

Add a mixed solution of 17.9 g of acrolein and 100 ml of THF, and react at room temperature for 3 to 5 hours. Cool the reaction solution and adjust the pH value to 5-6. The reaction solution is separated into layers, the organic phase is separated, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined. It was washed with saturated NaCl aqueous solution, dried and concentrated to obtain 60.2 g (GC content: 57.6%).

Add 10 g of anhydrous zinc chloride to a 3000 ml reaction flask, add 70 g of SOCl ₂ under the protection of N ₂ , and reflux for 0.5 hours. After cooling, add 1000ml cyclohexane and 500ml THF, add the mixture of 60.2g concentrate and 200ml cyclohexane obtained above at 0-5°C, and react at room temperature for 5 hours.

Cool the reaction solution, pour the reaction solution into ice water, separate the organic phase, extract the water phase with 1,2-dichloroethane, wash the combined organic phase with saturated NaCl solution, dry, and concentrate to obtain 87.6 g of brown liquid, GC Content: 39.34% (trans), 5.47% (cis), trans/cis=6.08:1.

Rectification: 29.8g light yellow liquid, GC content: 92.36% (trans), 2.17% (cis).

Bp: 64-68°C/10mmHg (trans), 59-64°C/10mmHg (cis).

Theoretical yield: 47.2g,

Actual yield: 28.2 g.

Actual Yield: 59.7%

Two, the synthesis of terbinafine hydrochloride

Add 40g of N-methylnaphthylmethylamine, 24.8g of sodium carbonate, 250ml of DMF into a 500ml reaction flask, cool to -5°C, add 38.5g of 1-chloro-6,6-dimethyl-2-heptene-4-yne , reacted for 0.5 hours. Then it is heated to 80-100° C. for reaction, and detected by TLC until the raw material 1-chloro-6,6-dimethyl-2-hepten-4-yne disappears, and the reaction ends.

Remove the solid in the reaction solution by filtration, dry the filtrate and concentrate to obtain 69.7g of a dark brown liquid, add 354ml of anhydrous ether, mix with the concentrated solution, then add an appropriate amount of water to wash, separate the water phase, wash the organic phase, dry and concentrate 65 g of brown viscous liquid was obtained. Dissolve in 650ml of absolute ethanol, slowly add 35ml of C ₂ H ₅ OH-HCl saturated solution under stirring, stir at room temperature for 20 minutes, and concentrate to dryness to obtain 94.4g of khaki solid.

The solid was dissolved with 278ml of isopropanol and 100ml of anhydrous ether, heated to dissolve, cooled to room temperature, then added with 500ml of ether, cooled to precipitate the solid, and filtered to obtain 68g of white powder (HPLC content: >99%).

Theoretical yield: 80.8g,

Actual yield: 68.0g,

Actual yield: 84.15%.

Example Three

1. 1-Chloro-6,6-dimethyl-2-heptene-4-yne

1000ml reaction flask, under _N2 protection, add 150mlTHF, 25.6g tert-butylacetylene. Add 250ml (1.52M) of vinylmagnesium bromide THF solution, heat up to a weak reflux state and react for 4-6 hours. Cool to -10~5°C.

Add a mixture of 17.9 g of acrolein and 100 ml of THF, and react at room temperature for 2 to 4 hours. Cool the reaction solution and adjust the pH value to 5-6. The reaction solution is separated into layers, the organic phase is separated, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined. It was washed with saturated NaCl aqueous solution, dried and concentrated to obtain 63.2 g (GC content: 57.6%).

Add 10 g of anhydrous zinc chloride to a 3000 ml reaction flask, add 70 g of SOCl ₂ under the protection of N ₂ , and reflux for 0.5 hours. After cooling, add 1000ml cyclohexane and 500ml THF, add the mixture of 63.2g concentrate and 200ml cyclohexane obtained above at 0-5°C, and react at room temperature for 5-7 hours.

Cool the reaction solution, pour the reaction solution into ice water, separate the organic phase, extract the water phase with 1,2-dichloroethane, wash the combined organic phase with saturated NaCl solution, dry, and concentrate to obtain 85.3 g of brown liquid, GC Content: 38.26% (trans), 5.44% (cis), trans/cis=7.03:1.

Rectification: 30.2g light yellow liquid, GC content: 91.53% (trans), 2.05% (cis).

Bp: 64-68°C/10mmHg (trans), 59-64°C/10mmHg (cis).

Theoretical yield: 48.7g,

Actual yield: 30.2 g.

Actual yield: 62.01%

Example 4

1. 1-Chloro-6,6-dimethyl-2-heptene-4-yne

In a 1000ml reaction flask, under N ₂ protection, 150mlTHF and 28.7g tert-butylacetylene were added. At room temperature, add 310ml (1.32M) of n-hexylmagnesium bromide THF solution dropwise, keep the reaction temperature not exceeding 35°C, and react at 53°C to a weak reflux state for 5 hours. Cool to -10～0℃.

Start to drop a mixture of 21.0 g of acrolein and 100 ml of THF, and react at room temperature for 3 to 5 hours. Cool the reaction solution and adjust the pH value to 5-6. The reaction solution is separated into layers, the organic phase is separated, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined. It was washed with saturated NaCl aqueous solution, dried and concentrated to obtain 71.5 g (GC content: 57.6%).

Add 15g of anhydrous zinc chloride into a 3000ml reaction flask, add 83.6g of SOCl ₂ under the protection of N ₂ , and reflux for 0.5 hours. After cooling, add 1000ml cyclohexane and 500ml THF, add dropwise the mixture of 71.5g concentrated solution and 200ml cyclohexane obtained above at 0-5°C, and react at room temperature for 3-6 hours.

Pour the reaction solution into ice water, separate the organic phase, extract the aqueous phase with 1,2-dichloroethane, wash the combined organic phase with saturated NaCl aqueous solution, dry, and concentrate to obtain 100.3 g of brown liquid, GC content: 38.53 % (trans), 7.11% (cis), trans/cis=5.42:1.

Rectification: 30.5g light yellow liquid, GC content: 91.52% (trans), 2.01% (cis).

Bp: 64-68°C/10mmHg (trans), 59-64°C/10mmHg (cis).

Theoretical yield: 55.1g,

Actual yield: 30.5 g.

Actual Yield: 55.4%

Two, the synthesis of Terbinafine hydrochloride

Add 20g of N-methyl-1-naphthylmethylamine, 130ml of DMF, and 19.7g of KHCO ₃ into a 250ml reaction bottle, and protect with nitrogen gas.

Cool to -5°C, add 18.4 g of 1-chloro-6,6-dimethyl-2-hepten-4-yne dropwise, and keep the temperature for 0.5 hours. Heat to 80-90°C for 4-6 hours, filter the reaction solution, and concentrate to obtain 42 g of black thick liquid. Add 50ml of dichloroethane to make it miscible, wash with water, 2% tartaric acid, and saturated NaHCO ₃ aqueous solution, dry, and concentrate to obtain 35.4g.

Dissolve the concentrated solution with 140ml of isopropanol, add 40ml of HCl-isopropanol saturated solution, stir, filter, and concentrate to obtain 45.9g of solid.

After heating and dissolving the solid with 50 g of isopropanol, the solid was precipitated by cooling. The solid was washed with ethylene glycol dimethyl ether to obtain 30.8 g of white powder (content HPLC>99%).

Theoretical yield: 33.7g,

Actual yield: 30.8g,

Actual yield: 91.4%.

Example 5

1. Synthesis of 1-chloro-6,6-dimethyl-2-heptene-4-yne

1000ml reaction bottle, under _N2 protection, add 150mlTHF, 24.8g tert-butylacetylene. Add 245ml (1.43M) of butyl lithium in THF, and heat up to weak reflux for 4 hours. cool down.

Add a mixed solution of 17.9 g of acrolein and 100 ml of THF, and react at room temperature for 3 to 5 hours. Cool the reaction solution and adjust the pH value to 5-6. The reaction solution is separated into layers, the organic phase is separated, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined. It was washed with saturated NaCl aqueous solution, dried and concentrated to obtain 60.2 g (GC content: 57.6%).

Add 10 g of anhydrous zinc chloride to a 3000 ml reaction flask, add 70 g of SOCl ₂ under the protection of N ₂ , and reflux for 0.5 hours. After cooling, add 1000ml of cyclohexane and 500ml of THF, add the mixture of 60.2g of the concentrate obtained above and 200ml of cyclohexane, and react at room temperature for 5 hours.

Cool the reaction solution, separate the organic phase, extract the water phase with 1,2-dichloroethane, wash the combined organic phase with saturated NaCl solution, dry, and concentrate to obtain 86.7g of brown liquid, GC content: 38.56% (trans ), 6.78% (cis), trans/cis=5.69:1.

Rectification: 26.7g light yellow liquid, GC content: 91.54% (trans), 2.56% (cis).

Bp: 64-68°C/10mmHg (trans), 59-64°C/10mmHg (cis).

Theoretical yield: 47.2g,

Actual yield: 26.7 g.

Actual Yield: 56.6%

Claims (4)

1. the synthetic route of a Terbinafine hydrochloride is characterized in that comprising the steps:

1) synthetic 1-halogen-6,6-dimethyl-2-heptene-4-alkynes:

In the time of-10～60 ℃, in organic solvent, be raw material, with lithium reagent RLi or alkyl with tertiary butyl acetylene

The mol ratio of Grignard reagent RMgX is 1: 0.5～3, reacts 0.5～36 hour, is converted into 3,3-dimethyl-1-

Butynyl lithium or 3,3-dimethyl-ethyl acetylene base Grignard reagent, described R base is C ₁～C ₁₀Straight chain or

Saturated or the undersaturated alkyl of chain, X is a halogen atom;

In the time of-20～40 ℃, in organic solvent, above-mentioned product again with acrolein reaction 1～30 hour, generate

6,6-dimethyl-1-heptene-4-alkynes-3-alcohol, wherein the consumption mol ratio of propenal is 0.5～5 of a tertiary butyl acetylene

Doubly;

At catalyzer ZnCl ₂Under the catalysis, in organic solvent, under-20 ℃～reflux temperature, use halide reagent halogen

Change rearrangement, halide reagent consumption mol ratio is 1～6 times of tertiary butyl acetylene, reacted 0.5～30 hour,

1-halogen-6,6-dimethyl-2-heptene-4-alkynes, wherein catalyzer ZnCl ₂The consumption mol ratio be tertiary butyl acetylene

0.2～4 times, described halide reagent is PCl ₅, POCl ₃, PBr ₃/ HBr, sulfur oxychloride or dichloride sulfone;

2) synthetic Terbinafine hydrochloride:

In organic solvent, N-alkyl-1-naphthalene methylamine and 1-halogen-6,6-dimethyl-2-heptan is rare-4-alkynes, alkaline bar

Carry out condensation at 10～140 ℃ under the part, then get the product Terbinafine hydrochloride with the HCl salify.

2. the synthetic route of a kind of Terbinafine hydrochloride as claimed in claim 1, it is characterized in that described organic solvent is alcohol, ether, hexanaphthene, tetrahydrofuran (THF), the N of toluene, benzene, low carbon chain, dinethylformamide, tetracol phenixin, methylene dichloride, sherwood oil, acetone, trichloromethane, normal hexane, normal heptane or dioxane.

3. the synthetic route of a kind of Terbinafine hydrochloride as claimed in claim 1 is characterized in that described alkali is Na ₂CO ₃, NaHCO ₃, K ₂CO ₃Or KHCO ₃And organic bases pyridine, triethylamine or Tributylamine.

4. the synthetic route of a kind of Terbinafine hydrochloride as claimed in claim 1 is characterized in that intermediate is without purification in the reaction process.