CN106631972A - Non-peptide tachykinin receptor antagonist preparation method - Google Patents

Abstract

The invention discloses a preparation method of a non-peptide tachykinin receptor antagonist, and its synthesis route is as follows: . The invention has simple and easy operation, cheap and easy-to-obtain raw materials, high reaction efficiency and good repeatability.

Description

A kind of preparation method of non-peptide tachykinin receptor antagonist

technical field

The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of a non-peptide tachykinin receptor antagonist.

Background technique

Substance P is a natural undecapeptide belonging to the tachykinin family of peptides. The tachykinins are named for their rapid contraction of extravascular smooth muscle. Tachykinins are distinguished by their conserved carboxy-terminal sequences. In addition to substance P, known mammalian tachykinins include neurokinin A and neurokinin B. Current nomenclature names the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3, respectively (NK-3). Antagonists of tachykinins, particularly substance P, are useful in the treatment of clinical conditions characterized by an excess of tachykinins, particularly substance P, including central nervous system disorders, nociception and pain, gastrointestinal disorders, bladder function disorders and Respiratory diseases. Attempts have been made to provide antagonists of substance P and other tachykinin receptors to more effectively treat the various diseases and conditions described above.

1-(1H-indol-3-yl)-2-amide-5-[3,5-bis(trifluoromethyl)phenyl]-3-one is an antagonist of a class of substance P, the world patent WO 9318023 discloses the preparation method of 1-(1H-indol-3-yl)-2-amide-5-[3,5-bis(trifluoromethyl)phenyl]-3-one and its application in central nervous system Diseases, nociception and pain, gastrointestinal disorders, bladder function disorders and respiratory diseases, but there are disadvantages such as low yield, complex reaction route, high cost, etc., so the present invention provides a cheap and easy-to-obtain raw material, route Synthesis of 1-(1H-indol-3-yl)-2-amide-5-[3,5-bis(trifluoromethyl)phenyl]-3-ones with simple operation and high yield method.

Contents of the invention

The technical problem solved by the present invention is to provide a preparation method of a non-peptide tachykinin receptor antagonist.

The present invention adopts following technical scheme in order to solve the above-mentioned technical problem, a kind of preparation method of non-peptide tachykinin receptor antagonist, it is characterized in that synthetic route is:

where R is or

The preparation method of the non-peptide tachykinin receptor antagonist of the present invention is characterized in that the specific steps of the synthesis process are:

(1) dissolving tryptophan in the HCl/CH ₃ OH mixed system, stirring overnight at room temperature, after the reaction was detected by TLC, concentrating under reduced pressure to obtain tryptophan methyl ester hydrochloride;

(2) Dissolve tryptophan methyl ester hydrochloride in CH ₃ OH, then add TEA and Boc ₂ O in sequence, then stir overnight at room temperature, TLC detects that after the reaction is completed, concentrate under reduced pressure, and the obtained crude product is dissolved in EtOAc , washed with water once, washed twice with sodium hydroxide solution, the organic phase was dried with anhydrous _Na2SO4 , filtered and concentrated to obtain N _- tert-butoxycarbonyl tryptophan methyl ester;

(3) Dissolve N-tert-butoxycarbonyl tryptophan methyl ester in CH ₃ OH/H ₂ O mixed system, then add sodium hydroxide, stir overnight at room temperature, concentrate the reaction mixture and extract it with EtOAc, The pH of the mixed system was adjusted to 6 with HCl, extracted twice with ethyl acetate, the organic phase was dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain N-tert-butoxycarbonyl tryptophan;

(4) Dissolve N-tert-butoxycarbonyl tryptophan in DMF, then add HATU, TEA and O,N-dimethylhydroxylamine, stir at room temperature overnight, add water and extract with EtOAc for 3 times, and use Dry _over anhydrous _Na2SO4 and concentrate under reduced pressure to give 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-2-(N,N-methylmethoxyamide) ;

(5) Dissolve dimethylmethane phosphonate in THF, cool to -70°C, add n-butyllithium dropwise under the protection of _N2 , keep the temperature of the reaction system below -55°C, after the dropwise addition is completed - Continue the reaction at 70°C for 1h, then add 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-2-(N,N-methylmethoxyamide at -70°C ), stirred and reacted for 0.5h, then added NH ₄ Cl solution, extracted twice with EtOAc, the organic phase was dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the obtained crude product was purified by column chromatography to obtain 1-(1H-ind Indol-3-yl)-2-(N-tert-butoxycarbonyl)-4-phosphodimethylester]-3-one;

(6) Dissolve 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-4-phosphate dimethyl ester]-3-one and LiCl in acetonitrile, then add DIPEA dropwise After reacting for 0.5 h at room temperature, add a THF solution of 3,5-bistrifluoromethylbenzaldehyde and stir for 0.5 h. After the reaction is completed, add water and extract twice with EtOAc. The organic phase is dried with anhydrous Na ₂ SO ₄ , Concentrated under reduced pressure, the resulting crude product was purified by column chromatography to obtain 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-4-ene-5-[3,5-bis( Trifluoromethyl)phenyl]-3-one;

(7) 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-4-ene-5-[3,5-bis(trifluoromethyl)phenyl]- The 3-ketone was dissolved in toluene, then tri-n-butyltin hydride was added, the reflux reaction was carried out overnight under the protection of N ₂ , concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain 1-(1H-indol-3-yl )-2-(N-tert-butoxycarbonyl)-5-[3,5-bis(trifluoromethyl)phenyl]-3-one;

(8) Dissolving 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-5-[3,5-bis(trifluoromethyl)phenyl]-3-one In the HCl/CH ₃ OH mixed system, stirred at room temperature for 2 h, concentrated under reduced pressure to obtain 1-(1H-indol-3-yl)-2-amino-5-[3,5-bis(trifluoromethyl ) phenyl]-3-one hydrochloride;

(9) 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-5-[3,5-bis(trifluoromethyl)phenyl]-3-one salt Salt, substituted carboxylic acid compounds, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid, triethylamine dissolved in dichloromethane, stirred at room temperature Until TLC detects that the reaction of the raw materials is complete, add water and extract with dichloromethane, the organic phase is separated and spin-dried, and the crude product is separated and purified by column chromatography to obtain the target product 1-(1H-indol-3-yl)-2-amide- 5-[3,5-bis(trifluoromethyl)phenyl]-3-ones.

Further preferably, the substituted carboxylic acid compound is aminoacetic acid, 3-pyridylacetic acid, piperazinylacetic acid or N,N-diethyl-3-propionic acid.

Compared with the prior art, the present invention has the following beneficial effects: simple and easy to operate, cheap and easy-to-obtain raw materials, high reaction efficiency and good repeatability.

detailed description

The above-mentioned contents of the present invention are described in further detail below through the embodiments, but this should not be interpreted as the scope of the above-mentioned themes of the present invention being limited to the following embodiments, and all technologies realized based on the above-mentioned contents of the present invention all belong to the scope of the present invention.

Example 1

Synthesis of tryptophan methyl ester hydrochloride

Tryptophan (15g, 73.5mmol) was dissolved in HCl/CH ₃ OH (4N) mixed system (200mL), stirred overnight at room temperature, after the completion of the reaction as detected by TLC, concentrated under reduced pressure to obtain tryptophan methyl ester hydrochloride Crude product 18.2g, yield 97.6%, pink solid. MS (ESI) m/z: 319.3 (M+H ⁺ ).

Example 2

Synthesis of N-tert-butoxycarbonyl tryptophan methyl ester

Tryptophan methyl ester hydrochloride (18.2g, 71.5mmol) was dissolved in CH ₃ OH (200mL), and TEA (29.8mL, 214.5mmol, 3eq) and Boc ₂ O (23.4g, 107.3mmol, 1.5eq), then stirred at room temperature overnight, TLC detected that the reaction was complete and then concentrated under reduced pressure, the resulting crude product was dissolved in EtOAc (200mL), washed successively with water (100mL) once, sodium hydroxide solution (0.5N, 100mL) Twice, the organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain 9.7 g of N-tert-butoxycarbonyl tryptophan methyl ester, with a yield of 42.7%. MS (ESI) m/z: 319.3 (M+H ⁺ ).

Example 3

Synthesis of N-tert-butoxycarbonyl tryptophan

N-tert-butoxycarbonyl tryptophan methyl ester (9.7 g, 30.5 mmol) was dissolved in CH ₃ OH/H ₂ O (100 mL/50 mL) mixed system, and then sodium hydroxide (1.8 g, 45.8 mmol) was added. After stirring overnight at room temperature, the reaction mixture was concentrated to 100 mL, which was then extracted with EtOAc (50 mL). Use HCl (1N) (aq) to adjust the pH of the reaction system to 6, then extract it with 100 mL ethyl acetate for 5 times, dry the organic phase with anhydrous Na ₂ SO ₄ , and concentrate under reduced pressure to obtain N-tert-butoxycarbonyl tryptamine Acid 7.3g, yield 78.7%. MS (ESI) m/z: 305.3 (M+H ⁺ ).

Example 4

Synthesis of 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-2-(N,N-methylmethoxyamide)

Dissolve N-tert-butoxycarbonyl tryptophan (7.3g, 24.0mmol) in DMF (100mL), then add HATU (36.0mmol, 1.5eq), TEA (13.3mL, 96.0mmol, 4eq) and O, N -Dimethylhydroxylamine (4.6g, 48.0mmol, 2eq), stirred at room temperature overnight, added 200mL of water and extracted 3 times with 150mL EtOAc, the organic phase was dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, the crude product was passed through the column Purification by chromatography (PE:EtOAc=7:1-5:1, v/v) gave 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-2-(N, N-methylmethoxyamide) 7.2g, yield 86.5%. MS (ESI) m/z: 348.2 (M+H ⁺ ).

Example 5

Synthesis of 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-4-phosphodimethylester]-3-one

Dimethylmethanephosphonate (6.4g, 51.9mmol, 6eq) was dissolved in THF (32mL), cooled to -70°C, and then n _- butyllithium (17.2mL, 43.0 mmol, 5eq) and keep the reaction temperature below -55°C. The reaction mixture was continued to react at -70°C for 1h, and then 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-2-(N,N-methyl methoxyamide) (3.0 g, 8.6 mmol), stirred for 0.5 h, then added 100 mL of saturated NH ₄ Cl solution, extracted twice with 100 mL EtOAc, dried the organic phase with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, The resulting crude product was purified by column chromatography (PE:EA=10:1-7:1, v/v) to obtain 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)- 2.6 g of dimethyl 4-phosphate]-3-one, yield 73.7%. MS (ESI) m/z: 411.2 (M+H ⁺ ).

Example 6

1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-4-ene-5-[3,5-bis(trifluoromethyl)phenyl]-3-one synthesis

1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-4-phosphate dimethyl]-3-one (2.6g, 6.3mmol) and LiCl (0.5g, 12.6 mmol, 2eq) was dissolved in acetonitrile, then DIPEA (1.6g, 34.5mmol, 2eq) was added dropwise, and 3,5-bistrifluoromethylbenzaldehyde (2.1g, 8.8mmol, 1.4 eq) in THF ( _23mL ), after the reaction was completed, 150mL of water was added, then extracted twice with 80mL EtOAc, the organic phase was dried with anhydrous _Na2SO4 , concentrated under reduced pressure, and the obtained crude product was analyzed by column chromatography (PE:EtOAc =20:1-10:1, v/v) purified to obtain 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-4-ene-5-[3,5- Bis(trifluoromethyl)phenyl]-3-one 2.2 g, yield 66.4%. MS (ESI) m/z: 527.2 (M+H ⁺ ).

Example 7

Synthesis of 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-5-[3,5-bis(trifluoromethyl)phenyl]-3-one

1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-4-ene-5-[3,5-bis(trifluoromethyl)phenyl]-3-one (2.2g, 4.2mmol) was dissolved in toluene, then tri-n-butyltin hydride (1.4g, 5mmol, 1.2eq) was added, under the protection of _N2 reflux reaction overnight, concentrated under reduced pressure, the resulting crude product was analyzed by column chromatography (PE:EtOAc=20:1-10:1, v/v) purified to give 1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-5-[3,5- Bis(trifluoromethyl)phenyl]-3-one 1.5 g, yield 62.9%. MS (ESI) m/z: 529.2 (M+H ⁺ ).

Example 8

Synthesis of 1-(1H-indol-3-yl)-2-amino-5-[3,5-bis(trifluoromethyl)phenyl]-3-one hydrochloride

1-(1H-indol-3-yl)-2-(N-tert-butoxycarbonyl)-5-[3,5-bis(trifluoromethyl)phenyl]-3-one (1.0g, 1.8mmol) was dissolved in HCl/CH ₃ OH mixed system (15mL), stirred at room temperature for 2h, and concentrated under reduced pressure to obtain 1-(1H-indol-3-yl)-2-amino-5-[3,5 - Bis(trifluoromethyl)phenyl]-3-one hydrochloride 0.8 g, yield 88.1%. MS (ESI) m/z: 429.2 (M+H ⁺ ).

Example 9

Synthesis of 1-(1H-indol-3-yl)-2-aminoacetamide-5-[3,5-bis(trifluoromethyl)phenyl]-3-one compound

46.4g (0.1 mol), TBTU 38g (0.12mol), triethylamine 31g (0.3mol), aminoacetic acid 8.2g (0.11mol) and dichloromethane 200mL, stirred at room temperature and reacted overnight, TLC monitoring raw materials reacted completely, added water 200mL, and then used Dichloromethane 200mL was extracted 4 times, the organic phase was combined, and the crude product obtained after the organic phase was evaporated was separated and purified by column chromatography (eluent: PE:EA=2:3, v/v) to obtain 1-(1H -21 g of -indol-3-yl)-2-aminoacetamide-5-[3,5-bis(trifluoromethyl)phenyl]-3-one, yield 43%. MS (ESI) m/z: 486.1 (M+H ⁺ ).

Example 10

Synthesis of 1-(1H-indol-3-yl)-2-(3-pyridylacetamide)-5-[3,5-bis(trifluoromethyl)phenyl]-3-one compound

46.4g (0.1 mol), TBTU 38g (0.12mol), triethylamine 31g (0.3mol), 3-pyridylacetic acid 15g (0.11mol) and dichloromethane 200mL, stirred at room temperature and reacted overnight, TLC monitored the complete reaction of raw materials, added 200mL of water, Then extract 4 times with dichloromethane 200mL, combine the organic phases, and the crude product obtained after the organic phase is evaporated is separated and purified by column chromatography (eluent: PE:EA=1:1, v/v) to obtain 1- (1H-indol-3-yl)-2-(3-pyridylacetamide)-5-[3,5-bis(trifluoromethyl)phenyl]-3-one 26g, yield 48%. MS (ESI) m/z: 548.2 (M+H ⁺ ).

Example 11

Synthesis of 1-(1H-indol-3-yl)-2-piperazinylacetamide-5-[3,5-bis(trifluoromethyl)phenyl]-3-one

46.4g (0.1 mol), TBTU 38g (0.12mol), triethylamine 31g (0.3mol), piperazinyl acetic acid 15.8g (0.11mol) and dichloromethane 200mL, stirred at room temperature and reacted overnight, TLC monitored the complete reaction of raw materials, added 200mL of water, Then extract 4 times with 200 mL of dichloromethane, combine the organic phases, and evaporate the organic phases to obtain a crude product that is separated and purified by column chromatography (eluent: PE:EA=2:3, v/v) to obtain 1- (1H-indol-3-yl)-2-piperazinylacetamide-5-[3,5-bis(trifluoromethyl)phenyl]-3-one 22g, yield 39%. MS (ESI) m/z: 555.5 (M+H ⁺ ).

Example 12

1-(1H-indol-3-yl)-2-(N,N-diethyl-3-propionamide)-5-[3,5-bis(trifluoromethyl)phenyl]-3- Ketone synthesis

46.4g (0.1 mol), TBTU 38g (0.12mol), triethylamine 31g (0.3mol), N,N-diethyl-3-propionic acid 15.8g (0.11mol) and dichloromethane 200mL, stirred at room temperature overnight, TLC monitoring The raw material reaction is complete, add water 200mL, then extract 4 times with dichloromethane 200mL, combine the organic phase, the crude product obtained after the organic phase is evaporated is separated and purified by column chromatography (eluent: PE:EA=1:1 , v/v) to obtain 1-(1H-indol-3-yl)-2-(N,N-diethyl-3-propionamide)-5-[3,5-bis(trifluoromethyl) Phenyl]-3-one 28g, yield 51%. MS (ESI) m/z: 556.2 (M+H ⁺ ).

The above embodiments have described the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What are described in the above embodiments and description are only to illustrate the principles of the present invention. Without departing from the scope of the principle of the present invention, there will be various changes and improvements in the present invention, and these changes and improvements all fall within the protection scope of the present invention.

Claims (3)

1. a kind of preparation method of non-peptide tachykinin receptor antagonists, it is characterised in that synthetic route is：

。

2. the preparation method of non-peptide tachykinin receptor antagonists according to claim 1, it is characterised in that building-up process Concretely comprise the following steps：

（1）Tryptophan is dissolved in into HCl/CH₃In OH mixed systems, it is stirred overnight under room temperature, TLC is detected after completion of the reaction, decompression It is concentrated to give tryptophan methyl ester hydrochloride；

（2）Tryptophan methyl ester hydrochloride is dissolved in into CH₃In OH, TEA and Boc is sequentially added₂O, was then stirred at room temperature Night, TLC detect concentrating under reduced pressure after completion of the reaction, and gained crude product is dissolved in EtOAc, washes with water successively 1 time, and sodium hydroxide is molten Liquid is washed 2 times, organic faciess anhydrous Na₂SO₄It is dried, filters, is concentrated to give N- tertbutyloxycarbonyl tryptophan methyl esters；

（3）N- tertbutyloxycarbonyl tryptophan methyl esters are dissolved in into CH₃OH/H₂In O mixed systems, sodium hydroxide, room temperature are subsequently adding Under be stirred overnight, after reactant mixture is concentrated by its with EtOAc extract, with HCl adjust mixed system pH value be 6, acetic acid Ethyl ester is extracted twice, organic faciess anhydrous Na₂SO₄It is dried, is concentrated under reduced pressure to give N- tertiary butyloxycarbonyl tryptophans；

（4）N- tertiary butyloxycarbonyl tryptophans are dissolved in DMF, HATU, TEA and O is added, N- dimethyl hydroxylamines, room temperature are stirred Mix reaction overnight, extracted 3 times with EtOAc after adding water, organic faciess anhydrous Na₂SO₄It is dried, is concentrated under reduced pressure to give 1-（1H- Yin Diindyl -3- bases）-2-（N- tertbutyloxycarbonyls）-2-（N, N- methyl methoxy base amide）；

（5）Dimethylmethane phosphonate ester is dissolved in THF, -70 DEG C are cooled to, in N₂The lower Deca n-BuLi of protection, keeps anti- System temperature is answered less than -55 DEG C, is continued reaction 1h after completion of dropping at -70 DEG C, then 1- is added at -70 DEG C（1H- indole- 3- bases）-2-（N- tertbutyloxycarbonyls）-2-（N, N- methyl methoxy base amide）, stirring reaction 0.5h is subsequently adding NH₄Cl solution, Extracted 2 times with EtOAc, organic faciess anhydrous Na₂SO₄It is dried, concentrating under reduced pressure, gained crude product Jing column chromatography purification obtain 1- （1H- indol-3-yls）-2-（N- tertbutyloxycarbonyls）- 4- dimethyl phosphates] -3- ketone；

（6）By 1-（1H- indol-3-yls）-2-（N- tertbutyloxycarbonyls）- 4- dimethyl phosphates] -3- ketone and LiCl be dissolved in acetonitrile In, then Deca DIPEA, adds the THF solution of 3,5- dual-trifluoromethyl benzaldehydes under room temperature condition after reacting 0.5h, and stirring is anti- 0.5h is answered, is added water after the completion of reaction and is extracted 2 times with EtOAc, organic faciess anhydrous Na₂SO₄It is dried, concentrating under reduced pressure, gained are slightly produced Product Jing column chromatography purification obtains 1-（1H- indol-3-yls）-2-（N- tertbutyloxycarbonyls）- 4- alkene -5- [3,5- bis- (trifluoromethyl) Phenyl] -3- ketone；

（7）By 1-（1H- indol-3-yls）-2-（N- tertbutyloxycarbonyls）- 4- alkene -5- [3,5- bis- (trifluoromethyl) phenyl] -3- ketone It is dissolved in toluene, adds three n-butyltin hydrides, in N₂Protect lower back flow reaction overnight, concentrating under reduced pressure, gained crude product Jing column chromatography purification obtains 1-（1H- indol-3-yls）-2-（N- tertbutyloxycarbonyls）- 5- [3,5- bis- (trifluoromethyl) phenyl] -3- Ketone；

（8）By 1-（1H- indol-3-yls）-2-（N- tertbutyloxycarbonyls）- 5- [3,5- bis- (trifluoromethyl) phenyl] -3- ketone dissolves In HCl/CH₃In OH mixed systems, 2h is stirred at room temperature, is concentrated under reduced pressure to give 1-（1H- indol-3-yls）- 2- amino -5- [3,5- bis- (trifluoromethyl) phenyl] -3- keto hydrochlorides；

（9）By 1-（1H- indol-3-yls）-2-（N- tertbutyloxycarbonyls）- 5- [3,5- bis- (trifluoromethyl) phenyl] -3- ketone hydrochloric acid Salt, substituted carboxylic acid class compound, O- BTA-N, N, N', N'- tetramethylurea Tetrafluoroboric acid, triethylamine are dissolved in dichloromethane In alkane, reaction is stirred at room temperature and detects that raw material reaction completely, is extracted with dichloromethane after adding water up to TLC, organic faciess are separated After be spin-dried for, crude product Jing column chromatography for separation purification obtain target product 1-（1H- indol-3-yls）- 2- amide -5- [bis- (trifluoros of 3,5- Methyl) phenyl] -3- ketone compounds.

3. the preparation method of non-peptide tachykinin receptor antagonists according to claim 2, it is characterised in that：Step（9） Described in substituted carboxylic acid class compound be glycine, 3- pyridyl acetic acids, piperazine guanidine-acetic acid or N, N- diethyl -3- third Acid.