WO2015192433A1

WO2015192433A1 - Process for synthesizing (r)-1-(naphthalene-1-group) ethylamine

Info

Publication number: WO2015192433A1
Application number: PCT/CN2014/082413
Authority: WO
Inventors: 黄志鸿; 徐亮; 李彦雄; 马卡⋅穆罕默德
Original assignee: 中山奕安泰医药科技有限公司
Priority date: 2014-06-18
Filing date: 2014-07-17
Publication date: 2015-12-23
Also published as: CN104045568A

Abstract

Provided is a process for synthesizing (R)-1-(naphthalene-1-group) ethylamine (I). The process comprises: using 1-acetonaphthone as a starting raw material; reducing the 1-acetonaphthone to (S)-1-(naphthalene-1-group) ethanol (II) by means of asymmetric hydrogenation, and then obtaining (R)-1-(naphthalene-1-group) ethylamine (I) with a high ee value after formation of (S)-1-(naphthalene-1-group) NOEPES derivative (III), azidation (IV) and hydrogenation reduction. The process has the characteristics of being easy to obtain raw materials and low in costs, and the like.

Description

- 豨虑 , - 基嶋 3 3⁄4

The present invention belongs to the field of pharmaceutical intermediates, and is mainly related to the novel process of 1 (naphthalene 1 -yl)ethylamine.

Cinacalcet hydrochloride (trade name Sensipar) was developed by NFS Ptarmaeeiiticals in the United States. It was approved by the FDA in March 2004. The main symptoms of the disease are: 1) Treatment of sputum Xieman's disease (CKD) "Kids see" secondary hyperparathyroidism; 2" treatment of hyperparalemia in patients with parathyroid cancer, its ft mechanism is activated in the parathyroid gland "« receptor, from Li hypoparathyroid ( PTH "curve"_; regulates the behavior of parathyroid calcium receptors, by increasing the sensitivity of receptors to calcium levels in the bloodstream, reducing levels of parathyroid hormone, calcium, phosphorus and calcium-phosphorus complexes.

The ft component of cinacalcet hydrochloride, Ciiwealcct, ft, N-((LR) 1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl) Phenyl)-l-amine Dmgs 2002, 27(9), 8311 83 discloses a method for preparing cinacalcet, and the main route is as follows:

WO P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P P

The preparation method of (naphthalene-1-yl)ethylamine tt is disclosed in WO2008/058235 A2, and its synthetic route is as follows:

1

Correction page (Article 91)

In such a process, (R)-l-(naphthalen-1-yl)ethylamine requires the use of (D) + naproxen for resolution, which will result in a higher cost of synthesis of cinacalcet.

Further, Synthesis (2008), (14), 2283-2287 also discloses the enzymatic synthesis of (R)-l-(naphthalen-1-yl)ethylamine, but there is a problem that it is difficult to industrialize.

J. Org. Chem., 2013, 78 (11), 5314-5327 also discloses a method for synthesizing (R)-l-(naphthalen-1-yl)ethylamine, which is synthesized as follows:

In this method, it is necessary to prepare (Z)-l ~ (naphthalen-1-yl)ethanone oxime, and the amount of catalyst used needs to be as high as 15%, and the reducing agent used is a tetrahydrofuran-borane solution, which is expensive. Not conducive to industrialization.

Although there have been many reports on the synthesis of (naphthyl-1-yl)ethylamine, they all have certain limitations, such as low yield, difficulty in industrialization, or relatively high cost of reagents used.

Summary of the invention

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel process for synthesizing (R)-l~(naphthalen-1-yl)ethylamine which is inexpensive and of good product quality.

The technical solution adopted by the present invention to solve the above problems is as follows:

A process for the synthesis of (i?)-l-(naphthalen-1-yl)ethylamine (I), including the following four steps involved in the synthetic route and route:

2

Correction page (Article 91)

(The solvent is used to dissolve anhydrous 1-naphthyl ethyl ketone and degassed by argon gas, and the molar ratio to anhydrous 1-naphthylethyl ketone is

1/100 ~ 1/100000 of catalyst Α, preferably (5, 5)-DIOPRuCl ₂ (5)-Me-BIMAH, added to the base with a molar ratio of anhydrous 1-naphthyl ethyl ketone of 20/1 ~ 30/1 C, charged with 8 ~ 30 bar of hydrogen, stirred at 0 ~ 50 °C for 8-16 h; filtered, solvent was removed to give off-white solid (naphthalen-1-yl) ethanol (II);

(2) The obtained 0)-1-(naphthalen-1-yl)ethanol (II) is dissolved in a solvent D, and then an acid-binding agent E, 0 is added in a molar ratio of 5/1 to 1/1 with II. The molar ratio of II to 1/1/1 sulfonyl chloride derivative F-solvent D was added dropwise at ~5 °C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1-8 h _; after quenching with saturated ammonium chloride solution, The organic layer was separated, the aqueous layer was extracted with methylene chloride, and the organic phase was combined, dried over anhydrous sodium sulfate, and dried to give a brown oil (S)-l-(naphthalen-1-yl)ethyl sulfonate derivative (III);

(3) Referring to Tetrahedron (1991), 47(9), 1603-1610, a method for converting a sulfonate to a configuration-overturned azide by a SN ₂ substitution reaction, which will be obtained (naphthalene-1-yl) The ethyl sulfonate derivative (ΠΙ) is dissolved in an anhydrous solvent G, and an azide H having a molar ratio of 2/1 to 5/1 is added, and the mixture is stirred at 30 to 60 ° C for 8 to 16 h, diluted with water, extracted with EtOAc, EtOAc (EtOAc)EtOAc.

(4) After dissolving (R)-l-(l-azidoethyl)naphthalene (IV) in methanol, hydrogenation is carried out by adding 1% to 80% of the catalyst I of the mass of IV, and stirring at room temperature for 16-40 hours _; The catalyst was removed by filtration, the solvent was evaporated, and the alumina column was passed quickly to afford (yield: <RTIgt;

In one embodiment, the catalyst A described in the step (1) is a BIMAH ligand and a dichlorophenyl ruthenium (II) complex produced by a phosphorus ligand such as DIOP, BI AP Josiphos, etc., and Zhongshan Aantai Pharmaceutical Technology Co., Ltd. The catalyst prepared by the method of Adv. Synth. Catal. 2011, 353, 495-500, preferably (<S, S)-DiopRuCl ₂ OS)-Me-BIMAH.

In one embodiment, the solvent B in the step (1) is any one or more of benzene, toluene, o-xylene, p-xylene, tert-butanol, isopropanol, ethanol, methanol, and acetonitrile. a mixture, preferably a mixed solvent of toluene and tert-butanol;

3

Correction page (Article 91) In one embodiment, the base C in the step (1) is a mixture of any one or more of potassium t-butoxide, sodium t-butoxide, cesium carbonate, potassium carbonate, sodium ethoxide, and sodium amide. Potassium tert-butoxide.

In one embodiment, the hydrogen pressure in step (1) is 8 to 30 bar, preferably 30 bar.

In one embodiment, the solvent D described in the step (2) is a mixture of any one or more of toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, chloroform, preferably dichloro Hyperthyroidism.

In one embodiment, the acid binding agent E in the step (2) is triethylamine, diisopropylethylamine, pyridine, N, N-lutidine, potassium carbonate, cesium carbonate, sodium carbonate, A mixture of any one or more of magnesium carbonate, potassium hydroxide and sodium hydroxide is preferably triethylamine.

In one embodiment, the sulfonyl chloride derivative F according to the step (2) is a mixture of any one or more of methylsulfonyl chloride, trifluoromethylsulfonyl chloride, p-toluenesulfonyl chloride, and benzenesulfonyl chloride. Preferably, methylsulfonyl chloride is used.

In one embodiment, the ratio of the (5)-1-(naphthalen-1-yl)ethanol (II) to the sulfonyl chloride derivative F in the step (2) is from 1/1 to 1/10, preferably. 1/1.5.

In one embodiment, the anhydrous solvent G in the step (3) is dimethyl sulfoxide, N, N-dimethylformamide, acetone, nitromethylpyrrolidone, tetrahydrofuran, acetonitrile. Mixture of any one or more, preferably dimethyl sulfoxide.

In one embodiment, the azide H of the step (3) is a mixture of any one or more of sodium azide, lithium azide, potassium azide, and diphenyl azide. , sodium azide is preferred.

In one embodiment, the catalyst I described in the step (4) is a palladium-containing catalyst or a nickel-containing catalyst, which is 20% Pd/C, 10% Pd/C, 5% Pd/C, 10% Pd (OH). A mixture of any one or more of ₂ / C, 20% Pd(OH) ₂ /C Raney nickel, preferably 10% Pd/C.

The method provided by the present invention has significant advantages:

1. Compared with the traditional splitting process, the splitting step is avoided, waste is avoided, and the cost is lower.

2. The process route is simple to operate and the process is easy to realize industrialization.

Concrete I»

The invention is further illustrated by the following examples. However, the scope of protection of the present invention is not considered to be limited to the specific embodiments described below. The simple derivation or equivalent alternatives made by those skilled in the art without departing from the basic idea of the invention are all within the scope of the invention.

Example 1

(1) In a 250 mL dry Shrek bottle, 1.70 g C lO mmol) of anhydrous 1-naphthylacetone with 30 mL of anhydrous A

Correction page (Article 91) The benzene was dissolved, argon gas was bubbled for 15 min, transferred to a 100 mL hydrogenation tube, and 10 mg of (& 5)-Diop-RuCl ₂ -(5)-Me-BIMAH catalyst and 70 mg (0.6 mmol) were added. Potassium tert-butoxide, fed to 30 bar of hydrogen, at 25. After stirring for 16 ho, the solvent was evaporated to give a pale-yellow oil (0S)-1-(naphthalen-1-yl)ethanol, which was solid after a long period of time, the conversion was 99.2%, and the ee value was 98% without purification. , proceed directly to the next step.

(2) Dissolve 1.72 g (10 mmol) of (naphthalen-1-yl)ethanol in 20 mL of dichloromethane, transfer to a 00 mL three-necked flask, and add 4.0 mL (30 mmol) of triethylamine. At 0 °C, 1.16 mL of methylsulfonyl chloride solution dissolved in 10 mL of dichloromethane was added dropwise. After the addition was completed, the temperature was raised to 25 ° C and stirred for 4 h. After quenching with 100 mL of a saturated aqueous solution of ammonium chloride, the organic layer was separated, and the aqueous layer was extracted with methylene chloride (30 mL x 3). The organic phase was combined and dried over anhydrous sodium sulfate. 2.41 g, yield 96.4%.

(3) 1.25 ₈ (5.011^1 ₀ 1) of (5)-1-(naphthalen-1-yl)ethyl methanesulfonate obtained in the step (2) as 15 mL of anhydrous dimethyl After the sulfoxide was dissolved, 0.65 g (10 mmol) of sodium azide was added, and the mixture was stirred at 60 ° C for 12 h. After adding 150 mL of purified water, ethyl acetate (50 mL×3) was combined, and the organic phase was combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a pale yellow oil (yield: 90.4%).

(4) In a 50 mL hydrogenation tube, dissolve 0.8 g of light yellow oil obtained in step (3) in 20 mL of methanol, add 80 mg of 10% Pd/C, and charge 1 bar of hydrogen, 25 °. C is stirred for 24 h. Filtration, the solvent was evaporated to give a pale yellow oil, and a crude over-alloyed alumina column yielded 0.62 g of a yellow oil with a yield of 89% and an ee value of 94%.

Example 2

(1) In a 250 mL dry Shrek bottle, 1.70 g (10 mmol) of anhydrous 1-naphthylacetone was dissolved in 30 mL of anhydrous toluene, argon gas was bubbled for 15 min, and transferred to 100 mL of hydrogenated solution. In the tube, add 11 mg of 5)-Diop-RuCl ₂ -(5)-i-Pr-BIMAH catalyst and 70 mg (0.6 mmol) of potassium t-butoxide, and pass 30 bar of hydrogen at 25 °C. After stirring for 16 h „filtering, the solvent was evaporated to give a pale yellow oil (5)-1-(naphthalen-1-yl)ethanol, which was solid after a long period of time, the conversion was 98.2%, and the ee value was 95% without purification. , proceed directly to the next step.'

(2) 1.72 g (10 mmol) of (5)-(naphthalen-1-yl)ethanol was dissolved in 20 mL of tetrahydrofuran, transferred to a 100 mL three-necked flask, and 2.4 mL (30 mmol) of pyridine, 0 was added. 1.16 mL of methylsulfonyl chloride solution dissolved in 10 mL of tetrahydrofuran was added dropwise to C, and the mixture was heated to 25 ° C for 4 h. After quenching with 100 mL of saturated ammonium chloride solution, the mixture was separated and the layers were separated. The aqueous layer was extracted with methylene chloride (30 mL x 3), and the organic phase was combined and dried over anhydrous sodium sulfate. 2.35 g, yield 94%.

(3) 1.25 _§ (5.0 dish 01) of (5)-1-(naphthalen-1-yl)ethyl methanesulfonate obtained in step (2) with 15 mL of anhydrous hydrazine, Ν-II After the methylformamide was dissolved, 0.49 g (10 mmol) of lithium azide was added and stirred at 60 ° C for 12 h.

5

Correction page (Article 91) After adding 150 mL of purified water, ethyl acetate (50 mL×3) was combined, and the organic phase was combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a pale yellow oil (yield: 83.3%).

(4) In a 50 mL hydrogenation tube, dissolve 0.8 g of light yellow oil obtained in step (3) in 20 mL of methanol, add 80 mg of 10% PdCOH;) ₂ / C, and fill with 1 bar Hydrogen was stirred at 25 ° C for 24 h. Filtration, the solvent was evaporated to give a pale-yellow oil, and a crude over-alloyed alumina column yielded 0.0.59 g of a yellow oil with a yield of 84.7% and an ee value of 92%. Example 3

(1) In a 250 mL dry Shrek bottle, 1.70 g (10 mmol) of anhydrous 1-naphthylacetone was dissolved in 30 mL of anhydrous o-xylene, and argon gas was bubbled for 15 min, then transferred to 100 mL. In the hydrogenation tube, 10 mg of 5)-Diop-RuCl ₂ -(5)- i-Bu-BIMAH catalyst and 70 mg (0.6 mmol) of sodium t-butoxide were added, and 30 bar of hydrogen was introduced at 25 ° C. Stir under 16h. Filtration and solvent removal gave a pale yellow oil ( -1-(naphthalen-1-yl)ethanol as a solid after a long time. The conversion was 97.3%, and the ee value was 94%. .

(2) 1.72 g (10 mmol) of (Λ)-l-(naphthalene-l-yl)ethanol was dissolved in 20 mL of dichloromethane, transferred to a 100 mL three-necked flask, and 1.68 g (30 mmol) of hydrogen was added. Potassium oxide, 1.16 mL of methylsulfonyl chloride solution dissolved in 10 mL of dichloromethane was added dropwise at 0 °C. After the addition was completed, the temperature was raised to 25 ° C and stirred for 4 h. The organic layer was extracted with aq. g, yield 88.4%.

(3) After dissolving 1.25 g (5.0 mmol) of (5)-1-(naphthalen-1-yl)ethyl methanesulfonate obtained in the step (2) in 15 mL of anhydrous tetrahydrofuran, 0.81 was added. G (10 mmol) of potassium azide was stirred at 60 ° C for 12 h. After adding 150 mL of purified water, ethyl acetate (50 mL×3) was combined, and the organic phase was combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a pale yellow oil (yield: 86.3%).

(4) In a 50 mL hydrogenation tube, dissolve 0.8 g of light yellow oil obtained in step (3) in 20 mL of methanol, add 70 mg of 20%, charge 1 bar of hydrogen, and stir at 25 °C. 24 h. Filtration, the solvent was evaporated to give a pale-yellow oil, and a crude over-alloyed alumina column yielded 0.56 g of a yellow oil with a yield of 80.4% and an ee value of 93%.

3⁄4i example 4

(1) In a 250 mL dry Shrek bottle, 1.70 g (10 mmol) of anhydrous 1-naphthylacetone was dissolved in 30 mL of anhydrous tert-butanol, argon gas was bubbled for 15 min, and transferred to 100 mL. In a hydrogenation tube, 10 mg of 5 Diop-RuCl ₂ -(5 Me-BIMAH catalyst and 70 mg (0.6 mmol) of potassium t-butoxide were added, 30 bar of hydrogen was introduced, and the mixture was stirred at 25 ° C for 16 h. The solvent was evaporated to give a pale yellow oil ( -1-(naphthalen-1-yl)ethanol, which was solid after a long period of time. The conversion was 99.6%, and the ee value was 96%, and the next reaction was carried out without purification. (2) Dissolve 1.72 g (10 mmol) of (Λ)-1-(naphthalen-1-yl)ethanol in 20 mL of chloroform, transfer to a 100 mL three-necked flask, and add 9.8 g (30 mmol) of cesium carbonate. At 0 °C, 1.16 mL of methylsulfonyl chloride solution dissolved in 10 mL of chloroform was added dropwise. After the addition was completed, the temperature was raised to 25 ° C and stirred for 4 h. The organic layer was extracted with aq. g, yield 86%.

(3) 1.25 g (5.0 mmol) of (5)-1-(naphthalen-1-yl)ethyl methanesulfonate obtained in the step (2) was dissolved in 15 mL of anhydrous dimethyl sulfoxide. Thereafter, 0.65 g (10 mmol) of sodium azide was added, and the mixture was stirred at 60 ° C for 12 h. After adding 150 mL of purified water, it was extracted with ethyl acetate (50 mL×3), and the organic phase was combined, dried over anhydrous sodium sulfate, and then evaporated to give a solvent.

(4) Dissolve 0.8 g of light yellow oil obtained in step (3) in 20 mL of methanol in a 50 mL hydrogenation tube, add 60 mg of Raney nickel, and charge 1 bar of hydrogen at 25 °C. Stir for 24 h. Filtration, the solvent was evaporated to give a pale-yellow oil, and the crude over-alloyed alumina column yielded 0.65 g of a yellow oil with a yield of 93.3% and an ee value of 94%.

Claims

Polar face request

1. A process for combining (小) small (naphthalene small base) ethylamine (I), which is characterized by the following: "Technology package" The following synthetic lines and routes contain "4:

(1) Dissolve water with Tao agent B. 1 Ethyl ketone and argon gas should be ft gas, add and no * 1-Cai ethyl ketone tt molar ratio is 1/100

- 1/100000 Xie Cuihua No. A, added with anhydrous 1-naphthyl ate»mol tt* 20/1 -30/1 tt base C, infused with 8 ~ 30 bar hydrogen, mixed at ~50 C 846 Filtration, the solvent is removed to obtain the rice white-1-(naphthalen-1-yl)ethanol (II);

(2) will get naphthalen-1-yl)ethanol (Π), after clearing the ship D Tao fresh" added with II ft 扉 t tfc for 5 / 1 ~ 1 / 1 binding acid cut E, 0 5 ^e C Add dropwise to the molar tt of II is /1 1 / 1 sulfonyl chloride derivative F Taotao D solution, after the completion of the drop chamber s following #i ~ § h _; a saturated m chloro ft 僚谆谆 ,, 3⁄4 organic layer The aqueous layer is extracted with methylene chloride, and the organic phase is combined with anhydrous sodium sulfate to dryness, and then dried to give a brown oil (5)-1 (Hocchi) ethyl phthalate ft biological complex 1) _;

(3) The (naphthalene 4 · yl) ethyl sulfonate derivative (ΠΙ) is dissolved in an anhydrous solvent G, and is added to a mixture with III « molar ratio of 2/1 to 5/1. After 3040 ^e C, the mixture is diluted with 8 1⁄2h» plus *, extracted with ethyl acetate, combined with organic phase, dried over anhydrous sodium sulfate, and clarified to obtain H color oil (Λ)-Ι-(Ι- Azidoethyl)cai(IV);

(4) After dissolving the small (1-azidoethyl)naphthalene methanol, add IV» extensive amount of 1%~ hidden 3⁄4 catalytic surface I to liquefy, and hold the temperature for 16~40h ₅ «Filtering hidden catalysis Cut off the solvent, quickly 3⁄4 through the alumina column to get a yellow oil 1»

(Cai Xiaoji) Ethylamine ( I )»

2, ft according to the extremely demanding 1 Weng process, the special is that the catalyst A is phosphine with # and ÷山安泰医科 tt has a secret division to produce ft B1MAH ligand and dichlorophenyl ruthenium (II) dimer Prepared catalyst.

3. The process of claim 1 wherein the clearing agent B is benzene, toluene, o-xylene, p-xylene, xylene, n-hexane, cyclohexane, tert-butanol, ethanol, methanol, Any one or more of the leaking compounds in acetonitrile

4. The process according to claim 1, wherein the alkali C is any one or more of sodium butoxide, tert-butanol, carbonate, carbon hydride, ethanol, and sodium Φ. Wet compound

5, the bar saw claim 1 to the process, which is characterized by the wide catch tt clear D as toluene, tetrahydrofuran, methylene chloride, N, N-: carbamide, gas imitation any one or more » «舍物》>

8

Correction page (Article 91)

6. The process of claim 1 wherein said acid scavenger E is triethylamine, diisopropylethylamine, pyridine, N,N-lutidine, potassium carbonate, cesium carbonate, a mixture of any one or more of sodium carbonate, magnesium carbonate, potassium hydroxide, and sodium hydroxide.

The process according to claim 1, wherein the sulfonyl chloride derivative F is any one or more of methylsulfonyl chloride, trifluoromethylsulfonyl chloride, p-toluenesulfonyl chloride, and benzenesulfonyl chloride. Kind of mixture.

8. The process according to claim 1, wherein the anhydrous solvent G is any one or more of dimethyl sulfoxide, N, N-dimethylformamide, acetone, and tetrahydrofuran. mixture.

9. The process of claim 1 wherein said azide H is any one or more of sodium azide, lithium azide, potassium azide, and diphenyl azide. Kind of mixture.

10. The process of claim 1 wherein said catalyst I is a palladium-containing catalyst or a nickel-containing catalyst which is 20% Pd/C, 10% Pd/C, 5% Pd/C, 10% Pd. A mixture of any one or more of (OH) ₂ /C, 20% Pd(OH) ₂ /C, Raney nickel.

9

Correction page (Article 91)