CN111039852A

CN111039852A - N-ethylpyridine methylamine hydrochloride crystal, preparation process and application thereof in preparation of tropicamide

Info

Publication number: CN111039852A
Application number: CN201911189787.XA
Authority: CN
Inventors: 詹祖金; 王希林
Original assignee: Carbogen Amcis Shanghai Co Ltd
Current assignee: Carbogen Amcis Shanghai Co Ltd
Priority date: 2019-11-28
Filing date: 2019-11-28
Publication date: 2020-04-21

Abstract

The invention discloses an N-ethylpyridine methylamine hydrochloride crystal, a preparation process and an application thereof in preparation of tropicamide, wherein N-ethylpyridine methylamine hydrochloride prepared from free N-ethylpyridine methylamine and hydrochloric acid is subjected to X-ray powder diffraction, and the crystal has diffraction peaks at about 9.73 degrees, 14.61 degrees, 17.98 degrees, 18.49 degrees, 20.36 degrees, 24.63 degrees and 27.21 degrees. Dissolving N-ethylpyridine methylamine in organic solvent, and stirring at room temperature or under heating until the materials are completely dissolved; slowly adding hydrochloric acid, and crystallizing; preserving heat, aging, filtering and drying to obtain the tropicamide key starting material N-ethylpyridine methylamine hydrochloride crystal. The method has the advantages of simple operation, obvious purification effect, low content of impurities of salt forms and crystal forms obtained by crystallization preparation, high purity, simple and convenient operation and contribution to industrial production.

Description

N-ethylpyridine methylamine hydrochloride crystal, preparation process and application thereof in preparation of tropicamide

Technical Field

The invention relates to a hydrochloric acid salt crystal of a tropicamide key starting material and a preparation process thereof, belonging to the technical field of medicine preparation.

Background

Tropicamide is an anticholinergic, a parasympathetic inhibitory drug, a preferred mydriatic drug for fundus examination and diagnosis in the field of ophthalmology, and also has the effect of ciliary muscle anesthesia.

In 1955, it was first synthesized by Roche and used in clinical manufacturers as a compound preparation besides alone. Tropicamide has many advantages such as rapid mydriasis and short recovery period compared with other mydriatic agents.

Physicochemical properties of tropicamide: the white crystal is powdery, bitter in taste, soluble in ethanol, chloroform and acetone, slightly soluble in water and insoluble in petroleum ether.

At present, the earliest method for synthesizing tropine amide disclosed is a method reported by Siliva Dei et al (Life Sciences, Vol, 58, No.23, PP.2147-2153), which takes salicylic acid as a raw material, firstly acetylates to protect hydroxyl, then reacts with N-ethylpyridine methylamine, and finally obtains tropine amide through deacetylation protection, wherein the reaction route is as shown in formula 1:

in 2017, Shanghai Tataceae technology Co., Ltd reports a synthetic route (formula 2) for synthesizing tropicamide by reduction, wherein the synthetic route takes diethyl phenylmalonate as a reaction raw material, the diethyl phenylmalonate reacts with N-ethylpyridine methylamine after two-step conversion, and the total yield is improved to 65%, and the synthetic route is shown as the formula 2:

both synthetic routes use N-ethylpyridine methylamine as the key starting material, with CAS numbers: 33403-97-3,

the molecular formula is: C8H12N 2: molecular weight: 136.20, having a chemical formula shown in formula 3:

the N-ethylpyridine methylamine is a light yellow oily liquid, the preparation process comprises the steps of carrying out condensation reaction on 4-pyridine formaldehyde and ethylamine to generate an imine intermediate 3, carrying out reduction reaction on the imine intermediate 3 through sodium borohydride to generate a crude product of the N-ethylpyridine methylamine, and carrying out further post-treatment and purification on the crude product to obtain an oily N-ethylpyridine methylamine product (shown in a formula 4).

At present, the industrialized post-treatment process is difficult to operate and purify and can only be purified by rectification, under 0.011atm, the boiling point of N-ethylpyridine methylamine is 103 ℃, under 0.005atm, the boiling point of the imine intermediate 3 is 87 ℃, the difference between the boiling points of the two materials is very small, the rectification and purification are difficult, the purification rate and the yield are not high, especially, the rectification energy consumption and the loss are large, and the cost is high; and N-ethylpyridine methylamine is an amine compound, is an organic base, is unstable after being stored for a long time, and is easily oxidized particularly during high-temperature rectification, so that the product purity is further reduced, and impurities are increased. Therefore, the commercial product prepared by the process usually contains more imine intermediates 3 and other related impurities, the purity is lower and generally does not exceed 95%, but as seen from the synthetic route of tropicamide, N-ethylpyridine methylamine is a key starting material of a key reaction step reported by a bulk drug product, and the quality and the purity of the N-ethylpyridine methylamine are directly related to the quality and the purity of the bulk drug product. Under the trend that the requirements of the current national policy on raw material medicines are more and more strict, the N-ethylpyridine methylamine with low purity hardly meets the market demand.

The oily N-ethylpyridine methylamine has high viscosity, and is difficult to transfer, split-package, store, transport and other operations, and the volatile unpleasant odor of organic amines is not friendly to workers in workshop operation, besides, the volatilized amine substances are easy to form smog urea derivative solids with carbon dioxide in the air, and the smog urea derivative solids are easy to block pipelines under the condition of airflow while polluting products, so that unnecessary accidents are caused, and therefore, the research and development of the high-purity, low-cost, and convenient-to-operate solidified N-ethylpyridine methylamine are significant and necessary;

the common purification method is crystallization, but N-ethylpyridine methylamine has a low melting point and is not suitable for crystallization, and the salt formation of the free base and acid is an effective means for solidification and purification considering that N-ethylpyridine methylamine is a free base per se. Therefore, the development of a salt forming method, which is simple in purification, better in stability and more environment-friendly, of the salt form of the starting material is a necessary trend.

Disclosure of Invention

The invention aims to provide hydrochloric acid salt of tropicamide key starting material N-ethylpyridine methylamine and a crystal form thereof, wherein the weak alkalinity of N-ethylpyridine methylamine is utilized to react with hydrochloric acid to generate an N-ethylpyridine methylamine hydrochloride crystal with excellent stability, the crystal is a solid with good granularity, does not have the unpleasant smell of volatile organic amines which is extremely unfriendly to workshop operators, does not have the irritation of hydrochloric acid gas, has good powder fluidity, is convenient to transfer, subpackage, store, transport and the like, particularly does not generate smog solids which are extremely easy to generate when liquid N-ethylpyridine methylamine is fed in the solid feeding process, further pollutes products and blocks pipelines, and is difficult to absorb moisture and is stable to store for a long time.

The N-ethylpyridine methylamine after salt formation has excellent impurity removal effect, the purity and yield of N-ethylpyridine methylamine hydrochloride are high, as shown in an HPLC spectrogram in figure 1, the commercially available N-ethylpyridine methylamine (on figure 1) has more than 10 impurities with the concentration of more than 0.15 percent under 254nm, the total product purity is less than 95.0 percent, the commercially available N-ethylpyridine methylamine contains more imine intermediates 3 and other organic impurities with similar product structures, and is difficult to remove by conventional purification means and rectification, after the N-ethylpyridine methylamine is salt-formed, the purity of crystals (under figure 1) is more than 99.99 percent, the purity is high, the impurity content is low, the product purification yield is more than 95 percent, the N-ethylpyridine methylamine salt-forming purification can greatly reduce energy consumption, the product purity is improved, the product cost is reduced, the competitiveness of the product is improved, and by controlling the quality and purity of key starting materials, the quality and purity of the raw material medicine of tropicamide can be effectively improved, so that the N-ethylpyridine methylamine hydrochloride is the optimal selection for purifying the N-ethylpyridine methylamine.

The invention also aims to provide a preparation process of the tropicamide key starting material N-ethylpyridine methylamine hydrochloride crystal, which has the advantages of simple operation, no need of distillation, delicacy and other large-energy-consumption operations, room temperature-based preparation of a stable crystal form, convenient operation and suitability for large-scale industrial production.

In order to achieve the purpose, the invention adopts the technical scheme that:

a tropicamide key starting material N-ethylpyridine methylamine hydrochloride is prepared by dissolving tropicamide key starting material N-ethylpyridine methylamine in an organic solvent, dropwise adding concentrated hydrochloric acid, filtering and drying to obtain N-ethylpyridine methylamine hydrochloride, wherein the preparation route is shown as formula 5:

the structural formula of the obtained tropicamide key starting material N-ethylpyridine methylamine hydrochloride is shown as a formula 6:

a crystal of tropicamide key starting material N-ethylpyridinemethylamine hydrochloride which has diffraction peaks at about 9.73 °, 14.61 °, 17.98 °, 18.49 °, 20.36 °, 24.63 °, 27.21 ° using X-ray powder diffraction;

further, using X-ray powder diffraction, the crystal had diffraction peaks at about 9.73 °, 14.61 °, 16.99 °, 17.98 °, 18.49 °, 19.54 °, 20.36 °, 23.15 °, 23.54 °, 24.63 °, 27.21 °, 27.80 °.

Without limitation, a typical example of the crystals of tropicamide key starting material, N-ethylpyridinemethylamine hydrochloride, of the present invention has an XRD pattern as shown in the following figure, which is characterized by the features shown in table 1.

Table 1:

2-Theta	d(A)	Height	I％	Area	I％	FWHM
							4.853	18.1953	359	9.1	1750	4.0	0.109
9.726	9.0864	2532	63.9	18719	42.7	0.132
							14.606	6.0595	1515	38.2	10647	24.3	0.130
16.989	5.2148	935	23.6	8404	19.2	0.185
							17.980	4.9295	573	14.5	4578	10.4	0.200
18.493	4.7937	2120	53.5	16535	37.7	0.144
							19.538	4.5398	1389	35.1	9547	21.8	0.136
20.364	4.3573	1028	25.9	7869	17.9	0.160
							21.096	4.2078	301	7.6	1142	2.6	0.168
23.150	3.8389	993	25.1	6075	13.8	0.134
							23.542	3.7759	885	22.3	6244	14.2	0.164
24.628	3.6118	3962	100.0	43874	100.0	0.198
							25.475	3.4936	552	13.9	3079	7.0	0.160
26.583	3.3504	1486	37.5	10449	23.8	0.146
							27.214	3.2742	2272	57.3	24273	55.3	0.204
27.803	3.2061	949	24.0	10887	24.8	0.266
							28.317	3.1491	605	15.3	2368	5.4	0.120
29.539	3.0216	409	10.3	1921	4.4	0.153
							30.452	2.9330	373	9.4	2039	4.6	0.182
31.412	2.8455	261	6.6	1136	2.6	0.212
							33.847	2.6461	649	16.4	6712	15.3	0.232
35.680	2.5143	335	8.5	2563	5.8	0.232
							36.311	2.4720	310	7.8	3632	8.3	0.383
37.555	2.3929	242	6.1	1906	4.3	0.317
							39.190	2.2968	721	18.2	7379	16.8	0.220
39.758	2.2653	450	11.4	2187	5.0	0.135
							40.255	2.2385	268	6.8	793	1.8	0.125
40.933	2.2030	274	6.9	2356	5.4	0.363
							41.502	2.1740	218	5.5	2125	4.8	0.457
43.869	2.0621	260	6.6	1455	3.3	0.194

the preparation method of the tropicamide key starting material N-ethylpyridine methylamine hydrochloride crystal comprises the following steps:

1) dissolving tropicamide key starting material N-ethylpyridine methylamine in organic solvent, and stirring at room temperature or heating (if needed) until the material is completely dissolved;

2) slowly adding hydrochloric acid, and crystallizing;

3) preserving heat, aging, filtering and drying to obtain the tropicamide key starting material N-ethylpyridine methylamine hydrochloride crystal.

The acid used is hydrochloric acid; the hydrochloric acid may be an aqueous solution of hydrogen chloride or a solution of an organic solvent.

The organic solvent is an alcohol or ester solvent and other organic solvents, including acetonitrile, dichloromethane and the like, and the alcohol is one or more of C1-C4 alcohols.

And (3) a crystallization process: adding N-ethylpyridine methylamine into an organic solvent, stirring at room temperature (heating to clear if necessary), slowly dropwise adding hydrochloric acid, precipitating a solid, stirring for 1-15 hours (adding seed crystals and carrying out gradient cooling to 0 ℃ if necessary, and adding seed crystals and carrying out gradient cooling on certain solvents with high room temperature solubility), filtering, and leaching with a small amount of organic solvent. Drying to obtain the N-ethylpyridine methylamine hydrochloride crystal.

According to the invention, the weak alkalinity of N-ethylpyridine methylamine is utilized to form salt with hydrochloric acid, so that the operation and loss caused by large energy consumption such as distillation and purification are avoided, the hydrochloride crystal form of the tropicamide key starting material N-ethylpyridine methylamine is successfully developed, the crystal form is regular and uniform, the impurity content is low, the purity is good, the yield is high, the salt form is not easy to damp, the storage stability is stable for a long time, and the crystal form is characterized.

The salt form and the crystal form of the invention are reported for the first time.

Has the advantages that: the method for preparing the tropicamide key starting material N-ethylpyridine methylamine hydrochloride crystal has the advantages of simple operation, obvious purification effect, low content of impurities of salt forms and crystal forms obtained by crystallization preparation, high purity, simple and convenient operation and contribution to industrial production.

Drawings

FIG. 1: HPLC spectra of N-ethylpyridyl methylamine hydrochloride and commercially available N-ethylpyridyl methylamine;

FIG. 2: an XRD spectrogram of the N-ethylpyridyl methylamine hydrochloride;

FIG. 3: HPLC chromatogram of N-ethylpyridyl methylamine hydrochloride.

Detailed Description

The invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention. The following example prepared the key starting material, N-ethylpyridylmethylamine hydrochloride, for tropicamide using the synthetic route shown in formula 7.

Example 1

Preparation of compound 1: adding 157.8g (1.4mol) of 4-pyridineformaldehyde and 2000mL of anhydrous ethanol into a 5000mL three-necked flask, stirring at room temperature to obtain a clear solution, controlling the temperature to be 0-10 ℃ by an ice-water bath, dropwise adding 214.6g (1.5mol) of 66% aqueous solution of ethylamine, finishing the dropwise addition, reacting for 1-2 hours, controlling the TLC point plate in a central manner, determining that the reaction is complete when the point of the raw material disappears, slowly adding 58.5g (1.5mol) of sodium borohydride in batches, finishing the addition, controlling the temperature to be 10-25 ℃, reacting for 1-2 hours, dropwise adding 300mL of purified water, stirring at room temperature overnight, controlling the TLC in a central manner, after the reaction is complete, carrying out vacuum concentration to remove the solvent, adding 2000mL of water, extracting with 2000mL of dichloromethane, washing the organic phase with 1500mL of saturated salt water, drying with anhydrous sodium sulfate, filtering, carrying out vacuum concentration on the filtrate to obtain 192.5g of dark yellow oily matter which, the crude product yield was 96.3%.

Purification of compound 1: 50.2g N-Ethyl pyridine methylamine crude product is further distilled under reduced pressure, and 28.1g of light yellow oily substance which is N-ethyl pyridine methylamine with purity of 94.8% and distillation yield of 56.2% can be obtained.

Example 2

Preparation of compound 2: 15.1g (0.11mol) of N-ethylpyridylmethylamine and 50mL of isopropanol are added into a 100mL three-necked flask, stirred at room temperature to obtain a light yellow clear solution, 14.25g (0.12mol) of 31% hydrochloric acid is slowly added dropwise, the solution is stirred at room temperature for 1-5 hours, filtered, the filter cake is washed with acetonitrile and dried in vacuum to obtain 17.5g of white crystals with the purity of 99.8% and the yield of 91.7%, and the white crystals have the XRD pattern shown in figure 2, and the characteristics of the XRD pattern are shown in Table 1.

Example 3

Preparation of compound 2: 10.2g (0.075mol) of pure N-ethylpyridine methylamine and 60mL of ethyl acetate are added into a 100mL three-necked bottle, a light yellow clear solution is obtained by stirring at room temperature, 9.7g (0.08mol) of 31% hydrochloric acid is slowly dripped, the dripping is finished, the mixture is stirred at room temperature for 1 to 5 hours, the filtration is carried out, a filter cake is washed by acetonitrile and dried in vacuum, and 11.44g of white crystals are obtained, the purity is 99.9 percent, and the yield is 88.7 percent.

Example 4

Preparation of compound 2: adding 30.2g N-ethylpyridine methylamine crude product and 100mL acetonitrile into a 250mL three-necked bottle, stirring at room temperature for 1 hour, heating to 60 ℃ to obtain a yellow clear solution, slowly dropwise adding 26.5g of 31% hydrochloric acid, completing dropwise adding, stirring for 1-5 hours, gradient cooling to room temperature, stirring for 1-3 hours, cooling to 0-5 ℃, stirring for 2-5 hours, filtering, washing a filter cake with methyl tert-butyl ether, and vacuum drying to obtain 30.4g of white crystals with the purity of 99.8%, wherein the yield is as follows: 89.0 percent.

Example 5

Preparation of tropicamide (compound 7): adding 20.4g (0.123mol) of tropine acid (compound 4) and 50mL of toluene into a 250mL three-necked bottle, heating to 50 ℃, adding 0.3g (0.003mol) of triethylamine, dropwise adding 19.0g (0.24mol) of acetyl chloride, reacting at 50 ℃ for 3 hours, dropwise adding 20.5g (0.17mol) of thionyl chloride, continuing to react for 5 hours, concentrating in vacuum to a small volume, adding 50mL of toluene, and cooling to room temperature; in another 500mL three-necked flask, 18.2g (0.134mol) of pure N-ethylpyridylamine (Compound 1),13.7g (0.136mol) of triethylamine and 100mL of toluene were placed, the mixture was cooled to 0 ℃, a solution of acetyltropine acid was added dropwise, the mixture was reacted at 0-10 ℃ overnight, 80mL of saturated saline was added and washed five times, 27g (0.23mol) of 31% hydrochloric acid was added to the organic phase, the mixture was heated to 90 ℃ and reacted overnight, the organic phase was separated, the mixture was washed with aqueous ammonia, dilute hydrochloric acid, saturated saline and purified water, the organic phase was concentrated under vacuum at 50 ℃, the concentrate was recrystallized from ethyl acetate/N-heptane, the cake was washed with N-heptane and dried under vacuum to obtain 26.5g of tropine amide with 98.8% purity and 75.9% yield.

Example 6

Preparation of tropicamide (compound 7): 28.7g (0.166mol) of N-ethylpyridine methylamine hydrochloride and 150mL of toluene are added to a 500mL three-necked flask, stirred at room temperature for 20 minutes, and heated to reflux; in another 250mL three-necked flask, 27.6g (0.166mol) of tropine acid (compound 4), 17.8g (0.176mol) of triethylamine and 100mL of toluene are added, under the condition of refluxing and water carrying, the solution of tropine acid is dripped into the solution of N-ethylpyridine methylamine hydrochloride (compound 2), the reaction is kept at the temperature for overnight, 200mL of common salt water is added for washing for 3 times, liquid separation is carried out, the organic phase is concentrated, ethanol N-heptane is added for recrystallization, the temperature is reduced to 0-5 ℃, stirring is carried out for 2-5 hours, filtering is carried out, the filter cake is washed with N-heptane and vacuum drying is carried out, thus obtaining 42.7g of tropine amide, the purity is 99.5%, and the yield: 90.4 percent.

Claims

N-ethylpyridine methylamine hydrochloride characterized in that: the N-ethylpyridine methylamine hydrochloride is prepared from free N-ethylpyridine methylamine and hydrochloric acid, and the structural formula is as follows:

。
2. a crystal of N-ethylpyridine methylamine hydrochloride, characterized in that: using X-ray powder diffraction, the crystals had diffraction peaks at about 9.73 °, 14.61 °, 17.98 °, 18.49 °, 20.36 °, 24.63 °, 27.21 °.
3. The crystal of N-ethylpyridinemethylamine hydrochloride as claimed in claim 2, characterized in that: using X-ray powder diffraction, the crystal had diffraction peaks at about 9.73 °, 14.61 °, 16.99 °, 17.98 °, 18.49 °, 19.54 °, 20.36 °, 23.15 °, 23.54 °, 24.63 °, 27.21 °, 27.80 °.
4. A process for the preparation of N-ethylpyridinemethylamine hydrochloride crystals as claimed in claim 2 or 3, characterised in that:

1) dissolving N-ethylpyridine methylamine in organic solvent, and stirring at room temperature or under heating until the materials are completely dissolved;

2) slowly adding hydrochloric acid, and crystallizing;

3) and preserving heat, aging, filtering and drying to obtain the tropicamide key starting material N-ethylpyridine methylamine hydrochloride crystal.
5. The process according to claim 4, characterized in that: the hydrochloric acid can be hydrochloric acid aqueous solution with mass fraction more than 15% or hydrogen chloride organic solution with mass fraction more than 5%.
6. The process according to claim 4, characterized in that: the weight ratio of the N-ethylpyridyl methylamine to the organic solvent is 1:2 to 1: 20.
7. The process according to claim 4, characterized in that: the amount of hydrogen chloride is 0.5-1.5 molar equivalents of N-ethylpyridine methylamine.
8. The process according to claim 4, characterized in that: the organic solvent is an alcohol or ester solvent.
9. Use of N-ethylpyridine methylamine hydrochloride as claimed in claim 1 in the preparation of tropicamide.
10. Use of the crystalline N-ethylpyridine methylamine hydrochloride according to any one of claims 2-3 in the preparation of tropicamide.