CN113999134A - Preparation method of formoterol, medicinal salt and intermediate thereof - Google Patents

Preparation method of formoterol, medicinal salt and intermediate thereof Download PDF

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CN113999134A
CN113999134A CN202111437905.1A CN202111437905A CN113999134A CN 113999134 A CN113999134 A CN 113999134A CN 202111437905 A CN202111437905 A CN 202111437905A CN 113999134 A CN113999134 A CN 113999134A
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formula
organic solvent
compound
stirring
ethyl acetate
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俞雄
肖杜政
郑广基
陈与华
袁西伦
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Shanghai Front Health Pharmaceutical Technology Co ltd
Guangzhou Jiankangyuan Respiratory Drug Engineering Technology Co ltd
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Shanghai Front Health Pharmaceutical Technology Co ltd
Guangzhou Jiankangyuan Respiratory Drug Engineering Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation

Abstract

The invention relates to a preparation method of formoterol, a medicinal salt thereof and an intermediate thereof. The purification method of the formoterol intermediate (the compound shown in the formula V) comprises the following steps: I) carrying out salt forming reaction on the crude compound shown in the formula V and fumaric acid in an organic solvent A to prepare fumarate of the compound shown in the formula V; II) carrying out a neutralization reaction of the fumarate salt of the compound shown in the formula V obtained in the step I) and a base in an organic solvent B to obtain the purified fumarate saltA compound of formula V; III) crystallizing the purified compound shown as the formula V obtained in the step II) in an organic solvent C to obtain a formoterol intermediate

Description

Preparation method of formoterol, medicinal salt and intermediate thereof
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to formoterol, a pharmaceutically acceptable salt thereof and a preparation method of an intermediate thereof.
Background
The chemical name of the pharmaceutically acceptable salt of formoterol (formula I) is: { N- [ 2-hydroxy-5- [ (RS) -1-hydroxy-2- [ (RS) -2- (4-methoxyphenyl) -1-methylethylamino ] ethyl ] phenyl ] } formamide fumarate dihydrate is a beta 2 sympathomimetic drug, and has the characteristics of long acting, high selectivity, stronger anti-inflammatory action, quick response, slight side effect and the like; having all the basic structures typical of sympathomimetic agents, the substituents on the amino nitrogen make them highly selective for the β 2 receptor. Pharmacological research shows that: formoterol fumarate dihydrate exerts an anti-inflammatory effect and a pulmonary edema-inhibiting effect by inhibiting the release of multiple links and inflammatory mediators in the pathological process of asthma. Clinical studies have shown that: formoterol is taken orally or inhaled, so that asthma (especially asthma at night) attack can be effectively controlled, and the effect can be maintained for more than 12 hours.
Figure BDA0003382413120000011
The synthesis process of the formoterol medicinal salt (formula I) is very complicated, and documents such as US3994974, ES2005492 and WO2008/035380A2 are reported. The european pharmacopoeia 2005 monograph discloses impurities of pharmaceutically acceptable salts of formoterol (formula i) and their limits, which are detailed in the following table:
Figure BDA0003382413120000021
the synthetic route disclosed in US3994974 is as follows:
Figure BDA0003382413120000031
the method has the following disadvantages:
1) no intermediate, final product and enantiomeric purity are disclosed;
2) the undesired isomers (RS, SR) are separated at the late stage of the synthesis and are not recoverable, leading to increased costs and increased pollution.
The synthesis route disclosed in ES2005492 is as follows:
Figure BDA0003382413120000041
this method has the following disadvantages:
1) harmful reagents such as hydrofluoric acid and crown ether and carcinogenic solvents such as benzene are used in the synthesis process, belong to expensive rare substances, have serious health and environmental problems, and are not suitable for amplification operation.
2) No information on the quality of formoterol fumarate is disclosed.
The synthetic route disclosed in WO2008/035380a2 is as follows:
Figure BDA0003382413120000042
the research shows that the method has the following problems when applied to the reaction for preparing the formoterol medicinal salt (formula I):
1) during the preparation of the compound of formula X from the starting material, it is necessary to carry out overnight trituration, multiple purifications and cumbersome operations. In addition, in the preparation and purification process of the compound of the formula X, the adsorption effect of activated carbon is not obvious, so that crystallization is difficult and incomplete, and the yield of the compound of the formula X is seriously influenced.
2) In the preparation process of the compound of the formula VI, formic acid is adopted, the reaction speed is low, the reaction is incomplete, the yield after purification is low, formic acid and acetic anhydride are adopted for reaction, and the acetic anhydride can react with the compound of the formula V to generate an acetylated byproduct (impurity C), so that the impurity C is not easy to remove, and the purity and the yield of the compound of the formula VI are influenced.
3) Multiple crystallization is adopted in the whole preparation process of the final product compound of formula I, the operation is complex under high-temperature conditions, the high-temperature heating of the compound of formula I in a solvent is extremely unstable, particularly in an alcohol solvent, impurities A and F are generated, the purification effect is not obvious, and the controllability of the amplification production time is poor, so that an ideal purification effect cannot be achieved.
4) The final product formula I is dried in vacuum at a temperature of 60 ℃, and the temperature is high, so that the risk of losing crystal water exists.
In conclusion, a better method for preparing and purifying important intermediates V and compounds shown in formula VII needs to be found, so that the yield and the purity are higher, and the method is suitable for industrial production.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a purification method of formoterol, medicinal salts thereof and important intermediates thereof, which has simple operation, high purity and high yield and is suitable for commercial production.
In particular, it is an object of the present invention to provide an improved process for purifying compounds of formula v with a high efficiency towards diastereoisomers.
It is a further object of the present invention to provide an improved process for the preparation of compounds of formula VI.
It is a further object of the present invention to provide an improved process for the purification of compounds of formula VII.
The invention also aims to provide the preparation method of the compound of the formula I, wherein the salt formation and the refining are completed in one step, and the preparation method is simple, convenient and efficient.
The above object of the present invention is achieved by the following technical solutions:
in one aspect, the present invention provides a method for purifying a formoterol intermediate (a compound of formula v), the method comprising the steps of:
Figure BDA0003382413120000061
I) carrying out salt forming reaction on the crude compound shown in the formula V and fumaric acid in an organic solvent A to prepare fumarate of the compound shown in the formula V;
II) carrying out a neutralization reaction on the fumarate of the compound shown in the formula V obtained in the step I) and alkali in an organic solvent B to obtain a purified compound shown in the formula V;
III) crystallizing the purified compound shown in the formula V obtained in the step II) in an organic solvent C to obtain a formoterol intermediate.
Preferably, in step I), the organic solvent a is an ester and an alcohol, preferably ethyl acetate and an alcohol, more preferably ethyl acetate and a lower alkanol (e.g. methanol, ethanol).
Preferably, in step I), the fumarate salt of the compound of formula v is prepared as follows:
heating the crude compound shown in the formula V and ethyl acetate to 60-75 ℃, adding fumaric acid and alcohol, stirring for dissolving, cooling to 20-35 ℃ after completely dissolving, stirring for 1-2h, continuously cooling to the internal temperature of-10-20 ℃, stirring for crystallizing for 1-2h to obtain the compound;
preferably, in step I), the fumarate salt of the compound of formula v is prepared as follows:
heating the crude compound shown in the formula V and ethyl acetate to 70-75 ℃, adding fumaric acid and alcohol, stirring for dissolving, cooling to 20-30 ℃ after completely dissolving, stirring for 1-2h, continuously cooling to the inner temperature of 0-10 ℃, stirring for crystallizing for 1-2h, and thus obtaining the compound.
Preferably, in step I), the alcohol in the organic solvent a is selected from one or more of methanol, ethanol and isopropanol, preferably methanol or ethanol, more preferably methanol.
Preferably, in step II), the purified compound of formula v is prepared as follows:
heating the fumarate of the compound shown in the formula V obtained in the step I) and alkali in an organic solvent B to the internal temperature of 20-40 ℃, and stirring for reacting for 4-6h to obtain the compound shown in the formula V;
preferably, in step II), the purified compound of formula v is prepared as follows:
heating the fumarate of the compound shown in the formula V obtained in the step I) and alkali in an organic solvent B to the internal temperature of 30-40 ℃, and stirring for reacting for 4-6h to obtain the compound.
Preferably, in step II), the organic solvent B is ethyl acetate, acetonitrile or dichloromethane, preferably dichloromethane or ethyl acetate, more preferably dichloromethane.
Preferably, in step II), the base is a 10 w/v% -20 w/v% sodium carbonate solution or a 10 w/v% -20 w/v% potassium carbonate solution, preferably a 10 w/v% -20 w/v% sodium carbonate solution, more preferably a 10 w/v% sodium carbonate solution.
Preferably, in step III), the formoterol intermediate is prepared as follows:
heating the purified compound shown in the formula V) obtained in the step II) in an organic solvent C to 50-70 ℃, stirring for dissolving, slowly cooling to the internal temperature of 15-35 ℃ after completely dissolving, and stirring for crystallizing for 2-3h to obtain a formoterol intermediate;
preferably, in step III), the formoterol intermediate is prepared as follows:
heating the purified compound shown in the formula V obtained in the step II) in an organic solvent C to 60-70 ℃, stirring for dissolving, slowly cooling to the internal temperature of 20-30 ℃ after complete dissolution, and stirring for crystallization for 2-3h to obtain the formoterol intermediate.
Preferably, in step III), the organic solvent C is 50 v/v% ethanol, ethyl acetate or isopropyl ether, preferably 50 v/v% ethanol or isopropyl ether, more preferably isopropyl ether.
Preferably, in step III), the ratio between the purified compound of formula v obtained in step II) and the organic solvent C is 1 g: 8.0mL-1 g: 15.0mL, preferably 1 g: 10.0mL-1 g: 12.0 mL.
Preferably, the preparation method of the crude compound shown in the formula V comprises the following steps:
1) carrying out condensation reaction on a compound shown as a formula II and a compound shown as a formula III to prepare a compound shown as a formula IV;
Figure BDA0003382413120000071
2) carrying out reduction reaction on the compound shown in the formula IV in the presence of reduced iron powder, ammonium chloride, absolute ethyl alcohol and water to obtain a crude compound shown in the formula V;
Figure BDA0003382413120000081
in another aspect, the present invention provides a method for purifying formoterol (a compound represented by formula vii), which comprises the steps of:
Figure BDA0003382413120000082
1) extruding the formoterol crude product by using nitrogen, filtering, and washing by using an organic solvent D;
2) concentrating the filtrate obtained in the step 1) under reduced pressure and evaporating;
3) adding the organic solvent E and the organic solvent F into the product obtained by evaporation in the step 2), stirring and pulping to obtain the formoterol.
Preferably, in step 1), the organic solvent D is a mixed solution of methanol and ethyl acetate, methanol, ethanol or tetrahydrofuran, and preferably a mixed solution of methanol and ethyl acetate.
Preferably, in step 2), the concentration under reduced pressure and evaporation are carried out under the condition of a water bath at 30-40 ℃, preferably 30-35 ℃.
Preferably, in step 3), the organic solvent E is dichloromethane, 1, 2-dichloroethane or chloroform, preferably dichloromethane;
preferably, in step 3), the organic solvent F is methanol, ethanol or isopropanol, preferably methanol;
preferably, in step 3), the volume ratio between the organic solvent E and the organic solvent F is 20: 1-30: 1, preferably 25: 1-30: 1.
preferably, in step 1), the preparation method of the crude formoterol comprises the following steps:
i) formylating a compound shown in a formula V and anhydrous formic acid in the presence of a condensing agent and an organic solvent G, and crystallizing to obtain a compound shown in a formula VI;
Figure BDA0003382413120000091
ii) carrying out reduction reaction on the compound shown in the formula VI in the presence of a catalyst and an organic solvent H to obtain a formoterol crude product (formoterol reaction liquid);
Figure BDA0003382413120000092
preferably, in step i), the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2- (7-oxabenzotriazol) -N, N' -tetramethyluronium Hexafluorophosphate (HATU) or Dicyclohexylcarbodiimide (DCC), preferably EDCI;
preferably, in step i), the organic solvent G is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform and ethyl acetate, preferably dichloromethane or 1, 2-dichloroethane, more preferably dichloromethane;
preferably, in step ii), the catalyst is 5 w/w% to 10 w/w% palladium on carbon or Raney nickel, preferably 5 w/w% to 10 w/w% palladium on carbon, more preferably 10 w/w% palladium on carbon;
preferably, in step ii), the organic solvent H is a mixed solution of methanol and ethyl acetate, methanol, ethanol or tetrahydrofuran, and preferably a mixed solution of methanol and ethyl acetate.
Preferably, in step i), the compound of formula v is a formoterol intermediate prepared by the purification method described above.
In a further aspect, the present invention provides a process for the preparation of formoterol fumarate (a compound of formula I), which comprises the steps of:
reacting the compound shown in the formula VII and fumaric acid in the presence of methanol, dimethyl sulfoxide (DMSO), an organic solvent I and water to generate salt, and crystallizing to obtain the compound.
Preferably, the organic solvent I is acetone, dichloromethane, butanone, ethyl acetate or acetonitrile, preferably butanone, ethyl acetate or acetonitrile, most preferably butanone.
Preferably, the formoterol obtained from the compound of formula vii by the aforementioned purification process.
In one embodiment, the reaction scheme for the preparation of formoterol fumarate (compound of formula I) is as follows:
Figure BDA0003382413120000101
compared with the prior art, the preparation method disclosed by the invention has the advantages of short route, simplicity, convenience and feasibility, can greatly reduce the production cost, does not relate to the use of dangerous or severely toxic reagents, finally prepares the target compound with high purity (RR, SS is more than or equal to 99.8 percent, RS and SR are less than or equal to 0.05 percent), and is suitable for industrial production and application.
Drawings
Embodiments of the present invention will be described in detail below with reference to the accompanying drawings, in which
FIG. 1 is a 1H-NMR spectrum of formoterol fumarate;
FIG. 2 is an HPLC chromatogram of impurity A and formoterol fumarate;
FIG. 3 is an HPLC chromatogram of impurity I and formoterol fumarate;
fig. 4 is a systematic adaptation map of impurity I and formoterol fumarate.
Detailed Description
The following is a detailed description of embodiments of the invention, but the invention can be implemented in many different ways, as defined and covered by the claims.
Example 1
1) Adding a compound (178.1g) of a formula II and a compound (161.7g) of a formula III into a reaction bottle, stirring, heating to an internal temperature of 90-100 ℃, reacting for 2-3h to an internal temperature of 120-130 ℃, reacting for 2-3h to complete reaction (HPLC (high performance liquid chromatography detection, and calculating by a peak area according to a normalization method, the reaction is considered to be complete when the compound (III) of the formula III) in a test sample is less than 10 percent), obtaining 320.5g of a compound (IV), cooling to 70 +/-5 ℃, and adding absolute ethyl alcohol (220mL) for dissolving so as to prepare for the next reaction.
Figure BDA0003382413120000111
2) Adding a compound (220mL) of a formula IV dissolved by absolute ethyl alcohol and absolute ethyl alcohol (1280mL) into a reaction bottle, stirring, adding reduced iron powder (199.7g), washing residues by absolute ethyl alcohol (1000mL), adding ammonium chloride (191.3g) and water (440mL), heating to an internal temperature of 75-85 ℃, reacting for 2-3h until the reaction is complete (HPLC detection, the peak area is calculated according to a normalization method, the compound (formula IV) in a sample is less than 5.0%, namely the reaction is complete), cooling to 75 +/-1 ℃, adding ethyl acetate, stirring and cooling to 20-30 ℃, adding ethyl acetate (550mL) for washing, filtering, combining all filtrates, concentrating and drying the obtained filtrate under reduced pressure at 50-60 ℃, removing ethyl acetate and ethanol, adding ethyl acetate (1650mL) and water (1100mL), stirring, separating and removing a water layer. The organic phase was washed 1 time with 10% aqueous sodium carbonate (1100mL), then with 20% aqueous sodium chloride (1100mL), then stirred with anhydrous magnesium sulfate (220g) and activated carbon (22g) for 1-2h, then filtered to remove the drying agent, washed 3 times with ethyl acetate (220mL), concentrated at 50-60 deg.C under reduced pressure and dried to give 296g of compound of formula V (A) as a red-brown sticky. Purity: 57.92%, diastereomer: 40.65 percent.
Figure BDA0003382413120000121
3) Step a): adding a compound (280g) shown as a formula V (A) and ethyl acetate (500mL) into a reaction bottle, stirring and dissolving, adding ethyl acetate (340mL), stirring, heating to an internal temperature of 60-65 ℃, adding fumaric acid (32.7g) and methanol (210mL) until a sticky substance is completely dissolved, cooling to 40 ℃ at a speed of 10 ℃ per hour, cooling to 20-30 ℃ in a water bath, stirring for 1-2h, cooling to an internal temperature of-10-0 ℃, stirring and crystallizing for 1-2h, filtering to obtain a solid, washing with ethyl acetate until the filtrate is light yellow, and drying in vacuum for 4-6h at a temperature of 50 +/-5 ℃ to obtain 190g of a light yellow solid.
Step b): adding the light yellow solid (130g) obtained in the step a), dichloromethane (650mL) and 10% sodium carbonate aqueous solution (650mL) into a reaction bottle, heating until an internal temperature of 20-30 ℃ generates a large amount of gas, stirring for 4-6h until the solid completely disappears, standing, separating, extracting an aqueous layer with dichloromethane (325mL) for 1 time, combining organic phases, washing the organic phase with 20% sodium chloride aqueous solution (650mL) for 2 times, and concentrating under reduced pressure at 40-50 ℃ to remove the solvent to obtain 116g of yellow oily matter.
Step c): adding the yellow oily matter (115g) obtained in the step b) and 50% ethanol (920mL) into a reaction bottle, heating to 50-60 ℃, stirring for dissolving, slowly cooling to the internal temperature of 15-20 ℃ after completely dissolving, keeping the internal temperature of 15-20 ℃, stirring for crystallizing for 2-3h, filtering to obtain a solid, washing the solid with 50% ethanol (115mL) for 3 times, and then drying in vacuum at 50 +/-5 ℃ for 4-6h to obtain 94.2g of a white solid, namely the compound shown in the formula V, wherein the yield is as follows: 81.91%, purity: 99.91%, diastereomer: 0.04 percent.
Figure BDA0003382413120000122
4) Reacting a compound of formula V(65g) And 1, 2-dichloroethane (300mL) was added to the reaction flask under N2Cooling the reaction solution to 0-10 ℃, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (44.9g) and 1, 2-dichloroethane (25mL), slowly adding anhydrous formic acid (12.0g) dropwise at an internal temperature of 0-10 ℃, after the dropwise addition is finished, keeping the internal temperature at 0-10 ℃, reacting for 1-2h until the reaction is complete (HPLC detection, the peak area is calculated according to a normalization method, the compound of formula V in the sample is less than 0.50 percent, namely the reaction is considered to be complete), then closing a cooling device, adding 10 percent sodium carbonate aqueous solution (275mL), heating to 20-30 ℃, stirring for 0.5-1.0h, separating an organic layer, extracting the water layer with 1, 2-dichloroethane (275mL), then combining with the 1, 2-dichloroethane layer, stirring and washing for 0.5-1.0h by using 10% sodium carbonate aqueous solution (275mL), then washing for 2 times by using 20% sodium chloride aqueous solution (325mL), concentrating the organic phase under reduced pressure at 40-50 ℃ to obtain a red brown sticky substance which is a crude product of the compound shown in the formula VI, adding 325mL of methanol, heating to 40-50 ℃ and stirring, cooling to 0-10 ℃ after the solid is dissolved, stirring for 1-2h, filtering to obtain a solid, washing the solid for 2 times by using 0-10 ℃ methanol (65mL), and then drying in vacuum for 4-8h at 45 +/-5 ℃ to obtain 56.2g of a white solid which is the compound shown in the formula VI, wherein the yield is that: 81.84%, purity: 99.94%, diastereomer: 0.02 percent.
Figure BDA0003382413120000131
5) Adding a compound (60g) shown in the formula VI, 5% palladium-carbon (12.0g) and tetrahydrofuran (720mL) into a reaction bottle, starting stirring, introducing nitrogen into a hydrogenation kettle for three times, wherein the pressure reaches 0.50-0.52 MPa each time, and introducing hydrogen into the hydrogenation kettle for three times, and the pressure reaches 0.50-0.52 MPa each time. Heating to 30-35 ℃ under the condition of introducing hydrogen to the pressure of 0.50-0.52 MPa, stirring for 4-5H until the reaction is complete (HPLC detection, the impurity H is less than 1.0% calculated by peak area according to a normalization method, the reaction can be considered to be complete), then removing the pressure, replacing once with nitrogen at 0.2-0.3 MPa, extruding and filtering the reaction liquid with nitrogen, washing the reaction bottle and the filter cake with tetrahydrofuran (300mL), concentrating and evaporating the filtrate under reduced pressure in a water bath condition of 30-35 ℃ for less than 4H, the vacuum degree is more than-0.09 MPa, then adding dichloromethane (300mL) and methanol (10mL), stirring, pulping for 3-4H under the temperature of 20-30 ℃, filtering to obtain a solid, washing the solid with dichloromethane (60mL) for 3 times, drying under the temperature of 40 +/-5 ℃ for 4-6H to obtain 32.2g of a white solid, namely a compound of the formula VII, yield: 81.75%, purity: 99.93%, diastereomer: 0.02%, impurity a: 0.02%, and no impurity B, C, D, E, F, G, H was detected.
Figure BDA0003382413120000141
6) Adding a compound (25g) shown as a formula VII, methanol (375mL) and dimethyl sulfoxide (DMSO) (50mL) into a reaction flask, adding fumaric acid (4.2g) and methanol (125mL) at 20-30 ℃, stirring for dissolving, stirring for 10min after solid is dissolved, adding water (50mL) and butanone (500mL), cooling to 0-10 ℃, stirring for 2-3h at 0-10 ℃ after solid is separated out, filtering, leaching the solid with butanone (75mL) for 3 times, and vacuum drying for 4-6h at 40 +/-5 ℃ to obtain 25.5g of a compound shown as a formula VII as a white solid, wherein the yield is as follows: 83.68%, purity: 99.95%, diastereomer: 0.02%, impurity a: 0.01% (correction factor 1.75), no impurity B, C, D, E, F, G, H was detected.
The measured spectral data of the compound of formula i are as follows:
1H-NMR(d6-DMSO)δ(ppm)：0.994(d,6H,J＝6.36Hz)，2.498(m,2H)，2.817(dd,2H,J＝9.3&12Hz)，2.872(dd,2H,J＝3.4&12Hz)，2.918(dd,2H,J＝4.4&13.2Hz)，3.115(m,2H)，3.719(s,6H)，4.673(dd,2H,J＝3.6&9Hz), 6.493(s,2H), 6.845(m,4H), 6.857(m,2H), 6.912(m,2H), 7.098(m,4H), 8.084(m,2H), 8.285(m,2H), 9.619(s,2H), the above spectral data demonstrate that the compound of formula i is formoterol fumarate, as shown in fig. 1.
Example 2
1) Adding 280g of the compound V (A) prepared in the step 2) in the example 1 and 500mL of ethyl acetate into a reaction bottle, stirring and dissolving, adding 340mL of ethyl acetate, stirring, heating to an internal temperature of 65-70 ℃, adding 32.7g of fumaric acid and 210mL of ethanol until the sticky substances are completely dissolved, cooling to 40 ℃ at a speed of 10 ℃ per hour, cooling to 30-35 ℃ in a water bath, stirring for 1-2h, cooling to an internal temperature of 0-10 ℃, stirring and crystallizing for 1-2h, filtering to obtain a solid, washing with ethyl acetate until the filtrate is light yellow, and vacuum-drying at a temperature of 50 +/-5 ℃ for 4-6h to obtain 190g of a light yellow solid.
Adding the light yellow solid (130g) obtained in the previous step, ethyl acetate (650mL) and 15% sodium carbonate aqueous solution (650mL) into a reaction bottle, heating to the internal temperature of 30-40 ℃ until a large amount of gas is generated, stirring for 4-6h until the solid completely disappears, standing, separating liquid, extracting the water layer with ethyl acetate (325mL) for 1 time, combining the organic phases, washing the organic phase with 20% sodium chloride aqueous solution (650mL) for 2 times, and concentrating under reduced pressure at 40-50 ℃ to remove the solvent to obtain 116g of yellow oily matter.
Adding the yellow oily substance (115g) obtained in the previous step and ethyl acetate (1150mL) into a reaction bottle, heating to 60-70 ℃, stirring for dissolving, slowly cooling to the internal temperature of 20-25 ℃ after completely dissolving, keeping at the internal temperature of 20-25 ℃, stirring for crystallization for 2-3h, filtering to obtain a solid, washing the solid with ethyl acetate (115mL) for 3 times, and then drying in vacuum at 50 +/-5 ℃ for 4-6h to obtain 94.8g of a white solid, namely a compound shown in formula V, wherein the yield is as follows: 82.43%, purity: 99.82%, diastereomer: 0.02 percent.
2) The compound of formula V (65g) and chloroform (300mL) were added to the reaction flask under N2The reaction solution was cooled to 0-10 ℃ under the conditions, and then 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (89.1g) and chloroform (25mL) were added, under the condition that the internal temperature is 0-10 ℃, slowly dropwise adding anhydrous formic acid (12.0g), after dropwise adding, keeping the internal temperature at 0-10 deg.C, reacting for 1-2h until the reaction is complete (HPLC detecting, calculating peak area according to normalization method, the compound of formula V in the sample is less than 0.50%, after the reaction was complete, the cooling apparatus was turned off, 10% aqueous sodium carbonate (275mL) was added, the temperature was raised to 20-30 deg.C, the mixture was stirred for 0.5-1.0h, the organic layer was separated, the aqueous layer was extracted with chloroform (275mL), the combined chloroform layer was combined, and the mixture was washed with 10% aqueous sodium carbonate (275mL) for 0.5-1.0h under stirring.Washing with 20% sodium chloride water solution (325mL) for 2 times, concentrating the organic phase at 40-50 deg.C under reduced pressure to obtain a brown sticky substance as a crude product of the compound of formula VI, adding 325mL methanol, heating to 40-50 deg.C, stirring, cooling to 0-10 deg.C after the solid is dissolved, stirring for 1-2h, filtering to obtain a solid, washing the solid with 0-10 deg.C methanol (65mL) for 2 times, and vacuum drying at 45 + -5 deg.C for 4-8h to obtain 56.6g of the compound of formula VI, with a yield of 82.42%, a purity of 99.86%, and a non-corresponding isomer of 0.05%.
3) Adding a compound (60g) of a formula VI, 10% palladium-carbon (12.0g), methanol (360mL) and ethyl acetate (360mL) into a reaction bottle, starting stirring, introducing nitrogen into a hydrogenation kettle for three times until the pressure reaches 0.50-0.52 MPa, and introducing hydrogen into the hydrogenation kettle for three times until the pressure reaches 0.50-0.52 MPa. Heating to 30-35 ℃ under the condition of introducing hydrogen to the pressure of 0.50-0.52 MPa, stirring for 4-5H until the reaction is complete (HPLC detection, the impurity H is less than 1.0% calculated by a peak area according to a normalization method, namely the reaction is complete), then removing the pressure, replacing once with nitrogen of 0.2-0.3 MPa, extruding and filtering the reaction liquid with nitrogen, washing the reaction bottle and the filter cake with a mixed solution of methanol (150mL) and ethyl acetate (150mL), concentrating and evaporating the filtrate under reduced pressure under the condition of 35-40 ℃ water bath for less than 4H, ensuring the vacuum degree to be more than-0.09 MPa, then adding 1, 2-dichloroethane (300mL) and methanol (12mL), stirring, pulping for 3-4H under the condition of 20-30 ℃, filtering to obtain a solid, washing the solid for 3 times with 1, 2-dichloroethane (60mL), and drying under vacuum for 4-6H under the condition of 40 +/-50 ℃, a white solid was obtained as 32.5g of the compound of formula VII in yield: 82.52%, purity: 99.89%, diastereomer: 0.05%, impurity a: 0.02%, and no impurity B, C, D, E, F, G, H was detected.
Example 3
1) High purity compound of formula V (65g) and ethyl acetate (300mL) were added to the reaction flask under N2Cooling the reaction solution to 0-10 deg.C, adding Dicyclohexylcarbodiimide (DCC) (62.3g) and ethyl acetate (25mL), slowly adding anhydrous formic acid (12.0g) dropwise at an internal temperature of 0-10 deg.C, maintaining the internal temperature at 0-10 deg.C after dropwise addition, and reacting for 1-2 hr until the temperature reaches 0-10 deg.CCompletely reacting (HPLC detecting, calculating peak area according to normalization method, determining that the reaction is complete if the formula V compound in the sample is less than 0.50%), closing cooling equipment, adding 10% sodium carbonate aqueous solution (275mL), heating to 20-30 deg.C, stirring for 0.5-1.0 hr, separating organic layer, extracting water layer with ethyl acetate (275mL), mixing with ethyl acetate layer, stirring and washing with 10% sodium carbonate aqueous solution (275mL) for 0.5-1.0 hr, washing with 20% sodium chloride aqueous solution (325mL) for 2 times, concentrating organic phase at 40-50 deg.C under reduced pressure to obtain red brown sticky substance as crude product of formula VI compound, adding 325mL of methanol, heating to 40-50 deg.C, stirring, dissolving the solid, cooling to 0-10 deg.C, stirring for 1-2 hr, filtering to obtain solid, adding 0-10 deg.C of methanol (65mL), washing for 2 times, and vacuum drying at 45 + -5 deg.C for 4-8h to obtain white solid of formula VI, 55.99g, yield: 81.53%, purity: 99.91%, diastereomer: 0.04 percent.
2) Adding a compound (60g) shown in the formula VI, raney nickel (12.0g) and tetrahydrofuran (720mL) into a reaction bottle, starting stirring, introducing nitrogen into a hydrogenation kettle for three times, wherein the pressure reaches 0.50-0.52 MPa each time, and introducing hydrogen into the hydrogenation kettle for three times, and the pressure reaches 0.50-0.52 MPa each time. Heating to 30-35 ℃ under the condition of introducing hydrogen to the pressure of 0.50-0.52 MPa, stirring for 4-5H until the reaction is complete (HPLC detection, the impurity H is less than 1.0% calculated by a peak area according to a normalization method, namely the reaction is complete), removing the pressure, replacing once with nitrogen of 0.2-0.3 MPa, extruding and filtering the reaction liquid by using nitrogen, washing the reaction bottle and the filter cake by using tetrahydrofuran (300mL), concentrating and evaporating the filtrate under the condition of 35 ℃ water bath under reduced pressure for less than 4H and the vacuum degree of more than-0.09 MPa, adding chloroform (300mL) and methanol (12mL), stirring, pulping for 3-4H under the condition of 20-30 ℃, filtering to obtain a solid, washing the solid for 3 times by using chloroform (60mL), and drying for 4-6H under the condition of 40 +/-5 ℃ in vacuum to obtain a white solid, namely a compound of the formula VII of 32.1g, wherein the yield is as follows: 81.50%, purity: 99.91%, diastereomer: 0.03%, impurity a: 0.02%, and no impurity B, C, D, E, F, G, H was detected.
Example 4
1) Adding 280g of the compound (A) of the formula V (A) prepared in the step 2) in the example 1 and 500mL of ethyl acetate into a reaction bottle, stirring and dissolving, adding 340mL of ethyl acetate, stirring, heating to an internal temperature of 70-75 ℃, adding 32.7g of fumaric acid and 210mL of ethanol until the sticky substances are completely dissolved, cooling to 40 ℃ at a rate of 10 ℃ per hour, cooling to 20-30 ℃ in a water bath, stirring for 1-2h, cooling to an internal temperature of 10-20 ℃, stirring and crystallizing for 1-2h, filtering to obtain a solid, washing with ethyl acetate until the filtrate is light yellow, and drying in vacuum for 4-6h at a temperature of 50 +/-5 ℃ to obtain 190g of a light yellow solid.
2) Adding the light yellow solid (130g) obtained in the previous step, acetonitrile (650mL) and 20% potassium carbonate aqueous solution (650mL) into a reaction bottle, heating to the internal temperature of 30-40 ℃ until a large amount of gas is generated, stirring for 4-6h until the solid completely disappears, standing, separating, extracting the water layer with acetonitrile (325mL) for 1 time, combining the organic phases, washing the organic phase with 20% sodium chloride aqueous solution (650mL) for 2 times, and concentrating under reduced pressure at 40-50 ℃ to remove the solvent to obtain 116g of yellow oily matter.
3) Adding the yellow oily substance (115g) obtained in the previous step and isopropyl ether (1380mL) into a reaction bottle, heating to 60-70 ℃, stirring for dissolving, slowly cooling to an internal temperature of 25-30 ℃ after completely dissolving, keeping at the internal temperature of 25-30 ℃, stirring for crystallization for 2-3h, filtering to obtain a solid, washing the solid with isopropyl ether (115mL) for 3 times, and drying in vacuum at 50 +/-5 ℃ for 4-6h to obtain a white solid, namely 93.8g of the compound shown in the formula V, wherein the yield is as follows: 81.57%, purity: 99.89%, diastereomer: 0.03 percent.
Example 5
Adding the compound (60g) of the formula VI prepared in the step 4) in the example 1, 10% palladium-carbon (12.0g) and ethanol (720mL) into a reaction bottle, starting stirring, introducing nitrogen into a hydrogenation kettle for three times until the pressure reaches 0.50-0.52 MPa, and introducing hydrogen into the hydrogenation kettle for three times until the pressure reaches 0.50-0.52 MPa. Heating to 30-35 ℃ under the condition of introducing hydrogen to the pressure of 0.50-0.52 MPa, stirring for 4-5H until the reaction is complete (HPLC detection, the impurity H is less than 1.0% calculated by peak area according to a normalization method, namely the reaction is complete), then removing the pressure, replacing once with nitrogen at 0.2-0.3 MPa, extruding and filtering the reaction liquid with nitrogen, washing the reaction bottle and the filter cake with ethanol (300mL), concentrating and evaporating the filtrate under reduced pressure in a water bath condition of 30-35 ℃ for less than 4H, the vacuum degree is more than-0.09 MPa, then adding dichloromethane (300mL) and methanol (15mL), stirring, pulping for 3-4H under the condition of 20-30 ℃, filtering to obtain a solid, washing the solid with dichloromethane (60mL) for 3 times, drying under vacuum at 40 + -5 deg.C for 4-6h to obtain 32.0g of compound of formula VII as white solid with yield: 81.25%, purity: 99.92%, diastereomer: 0.02%, impurity a: 0.02%, and no impurity B, C, D, E, F, G, H was detected.
Example 6
1) Adding the compound (1424.8g) of the formula II and the compound (1336.8g) of the formula III into a reaction bottle, stirring, heating to an internal temperature of 90-100 ℃, reacting for 2-3h to an internal temperature of 120-130 ℃, and reacting for 2-3h to complete (HPLC detection, the peak area is calculated according to a normalization method, and the compound (III) of the formula III) in the test sample is less than 10 percent, thus the reaction can be considered to be complete. ) 2480.2g of the compound of formula IV is obtained, and after cooling to 70 +/-5 ℃, absolute ethyl alcohol (1760mL) is added for dissolution for the next reaction.
2) Adding anhydrous ethanol-dissolved compound of formula IV (1760mL) and anhydrous ethanol (10240mL) into a reaction flask, stirring, adding reduced iron powder (1597.6g), washing the residue with anhydrous ethanol (8000mL), adding ammonium chloride (1530.4g) and water (3520mL), heating to an internal temperature of 75-85 ℃, and reacting for 2-3h until the reaction is complete (HPLC detection, the peak area is calculated according to a normalization method, and the compound of formula IV in a test sample is less than 5.0%, thus the reaction can be considered complete. ) Cooling to 75 + -1 deg.C, adding ethyl acetate, stirring, cooling to 20-30 deg.C, washing with ethyl acetate (4400mL), filtering, mixing all filtrates, concentrating the filtrate at 50-60 deg.C under reduced pressure, drying, removing ethyl acetate and ethanol, adding ethyl acetate (13200mL) and water (8800mL), stirring, and separating to remove water layer. The organic phase was washed 1 time with 10% aqueous sodium carbonate (8800mL), then 1 time with 20% aqueous sodium chloride (8800mL), then stirred for 1-2h with anhydrous magnesium sulfate (1760g) and activated charcoal (176g), then filtered to remove the drying agent, washed 3 times with ethyl acetate (1760mL), concentrated and dried at 50-60 deg.C under reduced pressure to give 2350.5g of compound of formula V (A) as a red-brown sticky. Purity: 59.92%, diastereomer: 32.65 percent.
3) Adding a compound (2240g) shown as a formula V (A) and ethyl acetate (4000mL) into a reaction bottle, stirring and dissolving, adding ethyl acetate (2720mL), stirring, heating to an internal temperature of 70-75 ℃, adding fumaric acid (261.6g) and isopropanol (1680mL) until the sticky substances are completely dissolved, cooling to 40 ℃ at a speed of 10 ℃ per hour, cooling to 20-30 ℃ in a water bath, stirring for 1-2h, cooling to an internal temperature of 0-10 ℃, stirring and crystallizing for 1-2h, filtering to obtain a solid, washing with ethyl acetate until the filtrate is light yellow, and drying in vacuum for 4-6h at a temperature of 50 +/-5 ℃ to obtain 1480.1g of a light yellow solid.
The pale yellow solid (1040g) obtained in the above step, methylene chloride (5200mL) and 10% potassium carbonate aqueous solution (5200mL) were added to a reaction flask, heated to an internal temperature of 30-40 ℃ to generate a large amount of gas, stirred for 4-6 hours until the solid completely disappeared, allowed to stand, separated into liquids, the aqueous layer was extracted with methylene chloride (2600mL) 1 time, the organic phases were combined, the organic phase was washed with 20% sodium chloride aqueous solution (5200mL) 2 times, and the solvent was removed by concentration under reduced pressure at 40-50 ℃ to obtain 928.6g of a yellow oil.
Adding the yellow oily substance (920g) obtained in the previous step and isopropyl ether (13800mL) into a reaction bottle, heating to 60-70 ℃, stirring for dissolving, slowly cooling to an internal temperature of 30-35 ℃ after the yellow oily substance and the isopropyl ether are completely dissolved, keeping the internal temperature at 30-35 ℃, stirring for crystallization for 2-3h, filtering to obtain a solid, washing the solid with isopropyl ether (920mL) for 3 times, and drying in vacuum at 50 +/-5 ℃ for 4-6h to obtain 710.4g of a compound with a white solid as a formula V, wherein the yield is: 77.17%, purity: 99.90%, diastereomer: 0.04 percent.
4) The compound of formula V (520g) and dichloromethane (2400mL) were added to a reaction flask at N2Cooling the reaction liquid to 0-10 ℃, adding 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (359.2g) and dichloromethane (200mL), slowly dripping anhydrous formic acid (96.0g) at the internal temperature of 0-10 ℃, keeping the internal temperature of 0-10 ℃ after dripping, reacting for 1-2h until the reaction is complete (HPLC detection, calculating the peak area according to a normalization method, and supplying the reaction liquid for reactionThe reaction is considered complete when the compound of formula V in the sample is less than 0.50%. ) Closing the cooling equipment, adding 10% sodium carbonate aqueous solution (2200mL), heating to 20-30 ℃, stirring for 0.5-1.0h, separating an organic layer, extracting an aqueous layer with dichloromethane (2200mL), combining with a dichloromethane layer, stirring and washing for 0.5-1.0h with 10% sodium carbonate aqueous solution (2200mL), washing for 2 times with 20% sodium chloride aqueous solution (2600mL), concentrating an organic phase at 40-50 ℃ under reduced pressure to obtain a reddish brown sticky substance which is a crude compound of the formula VI, adding methanol (2600mL), heating to 40-50 ℃, stirring, cooling to 0-10 ℃ after the solid is dissolved, stirring for 1-2h, filtering to obtain a solid, washing the solid with 0-10 ℃ methanol (520mL) for 2 times, drying in vacuum at 45 +/-5 ℃ for 4-8h to obtain 446.3g of a white solid which is the compound of the formula VI, yield: 81.25 percent. Purity: 99.91%, diastereomer: 0.02 percent.
5) Adding a compound of a formula VI (480g), 10% palladium-carbon (96.0g), methanol (2880mL) and ethyl acetate (2880mL) into a reaction bottle, starting stirring, introducing nitrogen into a hydrogenation kettle for three times until the pressure reaches 0.50-0.52 MPa, and introducing hydrogen into the hydrogenation kettle for three times until the pressure reaches 0.50-0.52 MPa. Heating to 30-35 ℃ under the condition of introducing hydrogen to the pressure of 0.50-0.52 MPa, stirring for 4-5H until the reaction is complete (HPLC detection, the impurity H is less than 1.0% calculated by peak area according to a normalization method, namely the reaction is complete), then removing the pressure, replacing once with nitrogen of 0.2-0.3 MPa, extruding and filtering the reaction liquid with nitrogen, washing the reaction bottle and filter cake with a mixed solution of methanol (1200mL) and ethyl acetate (1200mL), concentrating and evaporating the filtrate under reduced pressure under the condition of 30-35 ℃ water bath for less than 4H, wherein the vacuum degree is more than-0.09 MPa, adding 1, 2-dichloroethane (2400mL) and ethanol (96mL), stirring, pulping for 3-4H under the condition of 20-30 ℃, filtering to obtain a solid, washing the solid for 3 times with dichloromethane (480mL), drying for 4-6H under the condition of 40 +/-5 ℃ in vacuum, 269.4g of compound of formula VII was obtained as a white solid in yield: 85.51%, purity: 99.92%, diastereomer: 0.03%, impurity a: 0.02%, and no impurity B, C, D, E, F, G, H was detected.
6) Adding a compound shown in the formula VII (200g), methanol (3000mL) and dimethyl sulfoxide (DMSO) (400mL) into a reaction flask, adding fumaric acid (33.6g) and methanol (1000mL) at 20-30 ℃, stirring for dissolving, stirring for 10min after solid is dissolved, adding water (400mL) and ethyl acetate (4000mL), cooling to 0-10 ℃, stirring for 2-3h at 0-10 ℃ after solid is separated out, filtering, leaching the solid with butanone (600mL) for 3 times, and vacuum drying for 4-6h at 40 +/-5 ℃ to obtain a white solid, namely a compound shown in the formula III 210.8g, wherein the yield is as follows: 86.32%, purity: 99.93%, diastereomer (impurity I): 0.02%, impurity a: 0.02%, and no impurity B, C, D, E, F, G, H was detected.
The formoterol fumarate prepared in example 6 was subjected to high performance liquid chromatography. A high-efficiency chromatograph, an Agilent 1260I detector VWD, a chromatographic column Agilent zorbax SB-C8, 150 x 4.6mm, 5 μm; gradient elution is carried out by taking phosphate buffer (3.73 g of sodium dihydrogen phosphate monohydrate is taken, 1000ml of water is added for dissolution, phosphoric acid is added for adjusting the pH value to 3.3) as a mobile phase A, and acetonitrile as a mobile phase B, and the specific conditions are as follows:
time (min) Mobile phase A Mobile phase B (%)
0 () 16
10 84 16
37 30 70
40 84 16
55 84 16
The detection wavelength is 214 nm; flow rate: 1.0 mL/min; the column temperature was 30 ℃ as shown in FIG. 2, and the results are shown in Table 1 below:
TABLE 1 HPLC profile analysis of impurity A and formoterol fumarate
Figure BDA0003382413120000201
Figure BDA0003382413120000211
The formoterol fumarate prepared in example 6 was subjected to high performance liquid chromatography. A high performance chromatograph, Agilent1260 i detector VWD, chromatographic column Shodex Asahipak ODP-504D, 150 × 4.6mm, 5 μm; mixing acetonitrile: potassium sulfate buffer solution (12: 88) is used as a mobile phase; the detection wavelength is 225 nm; flow rate: 0.5 mL/min; the column temperature is 30 ℃, and is shown in detail in figure 3; system adaptability data is detailed in fig. 4; the results of the measurements are shown in Table 2 below:
TABLE 2 HPLC profile analysis of impurity I and formoterol fumarate
Figure BDA0003382413120000212
Formoterol fumarate prepared in example 6 was accelerated and long-term stability was investigated. Accelerated stability: test drug stability test box (immortal SHH-5005D), standing conditions: 40 +/-2 ℃ and 75% +/-5% RH; long-term stability: test drug stability test box (immortal SHH-5005D), standing conditions: 25 ℃ 2 ℃ 60% + -5% RH, the results are detailed in tables 3 and 4 below.
TABLE 3 Accelerator stability data statistics Table
Figure BDA0003382413120000213
Figure BDA0003382413120000221
And (4) conclusion: after the formoterol fumarate refined product sample is subjected to an accelerated test for 6 months, the properties, moisture, specific rotation, melting point, related substances, contents and isomers of the sample are not obviously changed compared with the sample in 0 month, and the sample meets the requirements.
TABLE 4 Long-term stability test data sheet
Figure BDA0003382413120000222
Figure BDA0003382413120000231
And (4) conclusion: after a long-term test for 12 months, the characters, moisture, specific rotation degree, melting point, related substances, contents and isomers of the formoterol fumarate refined product sample do not obviously change compared with the sample in 0 month, and the quality meets the requirements.
Comparative example 1
The experiment was carried out with reference to example 1, with the only difference being step 3), step a): fumaric acid (32.7g) and ethylene glycol (210mL) were added until the sticky mass was completely dissolved, resulting in a yield of the compound of formula V: 85.03%, purity: 98.32%, diastereomer: 0.10 percent.
In this example, it is seen that the use of ethylene glycol as organic solvent A gives a higher yield of the compound of formula V but with a lower purity and a less effective diastereomer removal.
Comparative example 2
The experiment was carried out with reference to example 1, with the only difference being 3) step a): continuously cooling to the internal temperature of-20 to-10 ℃, stirring and crystallizing for 1-2h, and finally obtaining the compound with the formula V: 82.14%, purity: 98.91%, diastereomer: 0.09 percent.
The experiment was carried out with reference to example 1, with the only difference being 3) step a): continuously cooling to the internal temperature of 20-30 ℃, stirring and crystallizing for 1-2h, and finally obtaining the compound of the formula V with the yield: 79.22%, purity: 99.92%, diastereomer: 0.04 percent.
From this example, it can be seen that the crystallization temperature is from-20 to-10 deg.C, the resulting compound of formula V has poor purity, poor isomer removal, and the crystallization temperature is from 20 to 30 deg.C, resulting in a lower yield of the compound of formula V.
Comparative example 3
The experiment was carried out with reference to example 1, with the only difference being step 3), step c): the yellow oil from step b) (115g) and acetonitrile (920mL) were added to the reaction flask, resulting in a yield of the compound of formula v: 85.27%, purity: 97.88%, diastereomer: 0.15 percent.
From this example, it is seen that acetonitrile is used as organic solvent C, and the compound of formula V obtained is high in yield, but low in purity and poor in diastereomer removal.
Comparative example 4
The experiment was conducted with reference to example 1, except that in step 5), the reaction solution was pressed out with nitrogen, filtered, the reaction flask and the filter cake were washed with a mixed solution of methanol (150mL) and ethyl acetate (150mL), and the filtrate was evaporated under reduced pressure in a water bath at 40-50 ℃ to give a compound of formula VII in yield: 81.11%, purity: 99.15%, diastereomer: 0.02%, impurity a: 0.12%, impurity F: 0.10%, and no impurity B, C, D, E, G, H was detected.
It can be seen from this example that the impurity level of the compound of formula VII is significantly higher at concentration temperatures of 40-50 ℃.
Comparative example 5
The experiment was performed with reference to example 1, except that in step 5), the filtrate was concentrated under reduced pressure and evaporated in a water bath at 30-35 ℃ for less than 4 hours at a vacuum degree of more than-0.09 MPa, n-hexane (300mL) and methanol (10mL) were added and stirred, slurried for 3-4 hours, filtered to obtain a solid, and the solid was washed 3 times with n-hexane (60mL) to obtain a yield of the compound of formula VII: 85.56%, purity: 98.00%, diastereomer: 0.03%, impurity a: 0.11%, impurity F: 0.09%, and no impurity B, C, D, E, G, H was detected.
From this example, it can be seen that the organic solvent D is n-hexane, and the compound of formula VII has high yield, low purity and high impurity content.
Comparative example 6
The experiment was performed with reference to example 1, except that in step 5), the filtrate was concentrated under reduced pressure in a 30-35 ℃ water bath for evaporation for less than 4 hours at a vacuum of greater than-0.09 MPa, dichloromethane (300mL) and ethyl acetate (10mL) were added and stirred, slurried for 3-4 hours, filtered to give a solid, and the solid was washed 3 times with dichloromethane (60mL) to give the compound of formula VII: 70.99%, purity: 99.94%, diastereomer: 0.02%, impurity a: 0.02%, and no impurity B, C, D, E, F, G, H was detected.
As seen in this example, the yield of the compound of formula VII is low when ethyl acetate is used as the organic solvent F.
Comparative example 7
The experiment was performed with reference to example 1, except that in step 5), n-hexane (300mL), methanol (10mL) were added and stirred, slurried for 3-4h, filtered to give a solid, and the solid was washed 3 times with n-hexane (60mL) to give the compound of formula VII in a yield: 85.77%, purity: 98.33%, diastereomer: 0.03%, impurity a: 0.13%, impurity F: 0.08%, and no impurity B, C, D, E, G, H was detected.
As seen from this example, when n-hexane was used as solvent E, the compound of formula VII was low in purity and high in impurity content.
Comparative example 8
The experiment was performed with reference to example 1, except that in step 5), dichloromethane (300mL) and dimethylsulfoxide (10mL) were further added, stirred, slurried for 3-4h, filtered to give a solid, and the solid was washed 3 times with dichloromethane (60mL) to give the compound of formula VII in yield: 72.12%, purity: 99.91%, diastereomer: 0.03%, impurity a: 0.03%, and no impurity B, C, D, E, F, G, H was detected.
As seen in this example, the yield of the compound of formula VII is low when dimethyl sulfoxide is used as solvent F.
Comparative example 9
Adding the compound (250g) of the formula V (A) obtained in the step 2) in the example 1 and isopropyl ether (2000mL) into a reaction bottle, heating to 50-60 ℃, stirring for dissolving, slowly reducing the internal temperature to 20-30 ℃ after completely dissolving, keeping the internal temperature at 20-30 ℃, stirring for 2-3h, not separating out a solid, stirring for 20h, separating out a solid, filtering to obtain a solid, washing the solid for 3 times with isopropyl ether (250mL), and then drying in vacuum at 50 +/-5 ℃ for 4-6h to obtain 32g of the compound of the formula V as a white solid, wherein the yield is low, the purity is 97.6%, and the non-corresponding isomer: 0.05 percent.
As seen from the example, the compound of formula V (A) is obtained without salification, and is directly crystallized by isopropyl ether in a free mode, so that the product is difficult to crystallize and has low purity.
Comparative example 10
Adding the compound (60g) of the formula VI obtained in the step 4) in the example 1, 10% palladium-carbon (12.0g), methanol (360mL) and ethyl acetate (360mL) into a reaction bottle, starting stirring, introducing nitrogen into a hydrogenation kettle for three times until the pressure reaches 0.50-0.52 MPa, and introducing hydrogen into the hydrogenation kettle for three times until the pressure reaches 0.50-0.52 MPa. Heating to 30-35 ℃ under the condition of introducing hydrogen to the pressure of 0.50-0.52 MPa, stirring for 4-5H until the reaction is complete (HPLC detection, the impurity H is less than 1.0% calculated by a peak area according to a normalization method, namely the reaction is complete), then removing the pressure, replacing once with nitrogen at 0.2-0.3 MPa, extruding and filtering the reaction solution with nitrogen, washing the reaction bottle and a filter cake with a mixed solution of methanol (150mL) and ethyl acetate (150mL), concentrating and evaporating the filtrate under reduced pressure at 30-35 ℃ for less than 4H under the condition of vacuum degree of more than-0.09 MPa, after the solvent is concentrated to dryness, directly adding methanol (600mL) and dimethyl sulfoxide (DMSO) (80mL) into the reaction bottle, adding fumaric acid (6.7g) and methanol (200mL) at 20-30 ℃, stirring and dissolving, stirring for 10min after the solid is dissolved, adding water (80mL) and butanone (800mL), cooling to 0-10 ℃, stirring for 2-3h at 0-10 ℃ after solid is separated out, filtering, leaching the solid with butanone (180mL) for 3 times, and vacuum drying at 40 +/-5 ℃ for 4-6h to obtain 27.6g of a white solid, namely a compound of formula I, with the yield: 70.35%, purity: 98.33%, diastereomer (impurity I): 0.02%, impurity a: 0.28%, impurity F: 0.21%, and no impurity B, C, D, E, G, H was detected.
From this example, it is seen that after the compound of formula i is prepared, the treatment is completed, and salt formation is directly performed without purification, so that the obtained compound of formula i has low purity and high impurity content.
Comparative example 11
Formoterol fumarate was prepared according to the method disclosed in WO2008/035380a2 in the background art, as follows:
1) preparation of 2- { benzyl- [2- (4-methoxyphenyl) -1-methylethyl ] amino } -1- (4-benzyloxy-3-nitrophenyl) -ethanol (formula IV)
188g (0.358mol) of 2- { benzyl- { 2-4-methoxyphenyl) -1-methylethyl ] amino } -1- (4-benzyloxy-3-nitrophenyl) -ethanone (X) and 2.5L of methanol were added to a 5L four-necked flask. To the stirred reaction mixture was added a total of 35g (0.921mol) of sodium borohydride in 10 aliquots at RT (25-30 ℃). After the addition, the resulting solution was stirred at 25-30 ℃ overnight. After methanol had been evaporated off, the residue obtained was dissolved in toluene (2.0L) and washed with water (2.5L). The toluene solution was then stirred with activated carbon and filtered. Concentration under reduced pressure and removal of toluene gave 205g of the compound of formula IV as a yellow oil. HPLC purity: RR and SS isomers: 50.21 percent; RS and SR isomers: 44.43 percent.
Purifying the compound of formula IV:
the above oily compound (205g) was added to a 2L four-necked flask and triturated with isopropyl ether (1200mL) overnight at room temperature (25-30 ℃). Filtration afforded a yellow solid (110 g). The solid compound was further purified by recrystallization from isopropyl ether (650mL) at 25-30 deg.C to give 80g of the compound of formula IV as a yellow crystal. HPLC purity: RR and SS isomers: 96.46 percent; RS and SR isomers: < 3.54%.
2) Preparation of 1- (3-amino-4-benzyloxyphenyl) -2- { benzyl- [2- (4-methoxyphenyl) -1-methylethyl ] amino } ethanol (V)
To a 2L stainless steel hydrogenation reactor were added the nitroalcohol derivative of formula IV (15g) and methanol (500mL), under nitrogen, and to this solution was added Raney nickel catalyst (3-5g) (previously washed with methanol). Then hydrogen was introduced and the pressure was adjusted to 40-60psi H2Hydrogenation under pressure and at RT (25-30 ℃). After the hydrogenation was complete, the catalyst was removed by filtration under nitrogen and the filtrate was concentrated under reduced pressure to remove the solvent to give a tan compound as crude 10.9g of the compound of formula V. HPLC purity: RR and SS isomers: 97.74%, RS and SR isomers: 0.79 percent
Purifying the compound of formula V:
the crude product (10.9g) was dissolved in isopropyl ether (54.5mL) at 65-70 deg.C, charcoal was added and the mixture was stirred and filtered, then the filtrate was slowly cooled to room temperature (25-30 deg.C) and filtered to give 8.7g of compound of formula V as tan crystals. MR: 97.5-99.5 ℃, HPLC purity: RR and SS isomers: 97.85%, RS and SR isomers: 0.64 percent
3) Preparation of N- [5- (2- { benzyl [2- (4-methoxyphenyl) -1-methylethyl ] amino } -1-hydroxyethyl) -2-benzyloxyphenyl ] (VI)
Acetic anhydride (31.52g) was added to a 1L four-necked flask and cooled to 0 ℃ with a cooling bath. Formic acid (15.96mL) was added dropwise at a rate of about 1 mL/min with vigorous stirring to maintain the temperature of the reaction mixture below 5 ℃. After 30 minutes, the reaction was heated to 50-55 ℃. After 2 hours, the reaction was cooled to 5-10 ℃. To this solution was added a pre-dissolved solution of the crystalline amino derivative of formula V (42g) in THF (260mL) at 5-10 deg.C. After addition was complete, the cooling bath was removed and the reaction was stirred at room temperature overnight. The solvent was removed by concentration under reduced pressure, and the oily residue was dissolved in ethyl acetate and washed with 5% aqueous sodium bicarbonate solution and sodium carbonate solution, in that order. The organic layer was stirred with activated carbon and then filtered to give a clear solution. The solvent was removed by concentration under reduced pressure and crystallized from isopropyl ether to give 42.0g of a crystalline compound of the formula VI. The product was recrystallized from isopropanol (420mL) at 25-30 deg.C to give 40.2g of the white crystalline compound of formula VI. MR: 112.7-114.2 ℃, HPLC purity: RR and SS isomers: 98.07%, RS and SR isomers: 0.56% and acetylated impurities 1.5%.
4) Preparation of N- (2-hydroxy-5- { 1-hydroxy-2- [2- (4-methoxyphenyl) -1-methylethylamino ] ethyl } phenylcarboxamide VII
A1L stainless steel hydrogenation reactor was charged with a pre-dissolved solution of the crystalline compound of formula VI (40g) in ethyl acetate (250 mL). To this solution was added a suspension of 10% palladium on charcoal (16g) in methanol (250 mL). And hydrogenated at 40-60 psi. After the hydrogenation was completed, the catalyst was removed by filtration under nitrogen, and the filtrate was concentrated under reduced pressure at 30 to 40 ℃ to remove the solvent. The resulting compound was cooled to 35-40 deg.C, added ethyl acetate (350mL) followed by isopropanol (250mL) and crystallized at 30-35 deg.C to give 15g of the compound of formula VII as a white solid. HPLC purity: RR and SS: 99.13%, RS and SR isomers: 0.29%, impurity "a": 0.23%, impurity "C": 0.19%, impurity "F": 0.07%, impurity "E": 0.04%, the remaining impurities B, D, G, H were not detected.
5) Preparation of formoterol fumarate I (B)
Into a 500mL four-necked flask were charged the above white solid formula VII (15g) and toluene (150 mL). To the stirred suspension at room temperature (25-30 ℃ C.), a solution of previously dissolved fumaric acid (2.40g) in isopropanol (30mL) was added. After stirring at room temperature for 5 hours, filtration was carried out, the resulting material was stirred with 95% aqueous isopropanol (300ml) and heated to 65-75 ℃ for 1-2 hours, then the reaction mass was cooled to 40-45 ℃ for 1-2 hours and filtered. The wet mass was placed in a flask and acetonitrile (460mL) was added, stirred, and heated to 75-80 ℃. Keeping for 1-2h, cooling the reactant to 40-45 ℃, keeping for 1-2h, filtering, and vacuum drying at 60 ℃ to obtain 10.1g of compound I (B). HPLC purity: RR and SS: 99.08%, RS and SR isomers: 0.26%, impurity "a": 0.29%, impurity "C": 0.17%, impurity "F": 0.15%, impurity "E": 0.02%, the remaining impurities B, D, G, H were not detected.
6) Preparation of formoterol fumarate dihydrate I (C)
Grinding the compound of formula I (B) (10.1g) and water (64mL) for 30 minutes at RT (25-30 ℃), then filtering, washing the wet filter cake with water, and drying in vacuum at 60 ℃ to obtain 10.0g of a white solid, namely the compound of formula I (C). HPLC purity: 99.15%, impurity "a": 0.23%, impurity "C": 0.16%, impurity "F": 0.14%, impurity "E": 0.02%, the remaining impurities B, D, G, H were not detected. Isomer purity (HPLC): RR and SS: 99.10%, RS and SR isomers: 0.28 percent.
According to the preparation process, multiple crystallization, high-temperature conditions and complex operation are adopted in the whole preparation process; the formoterol VII has low preparation purity, a plurality of impurities are detected, and the subsequent purification needs to be carried out for a plurality of times, so that the production cost is increased; the preparation of the I (B) is carried out under the high-temperature condition, so that the product has poor stability and the impurity growth is obvious; and the I (C) is dried under vacuum at 60 ℃ with the risk of losing crystal water.
The above-described embodiments are merely preferred embodiments of the present invention, and should not be construed as limiting the present invention, and features in the embodiments and examples in the present application may be arbitrarily combined with each other without conflict. The technical scheme of the invention is described in the claims, and the technical equivalents including technical features in the technical scheme described in the claims are used as the protection scope, namely, equivalent replacement and improvement in the scope are also within the protection scope of the invention.

Claims (10)

1. A process for the purification of formoterol (a compound of formula v II) comprising the steps of:
Figure FDA0003382413110000011
1) extruding the formoterol crude product by using nitrogen, filtering, and washing by using an organic solvent D;
2) concentrating the filtrate obtained in the step 1) under reduced pressure and evaporating;
3) adding the organic solvent E and the organic solvent F into the product obtained by evaporation in the step 2), stirring and pulping to obtain the formoterol.
2. The method according to claim 1, wherein in step 1), the organic solvent D is a mixed solution of methanol and ethyl acetate, methanol, ethanol or tetrahydrofuran, preferably a mixed solution of methanol and ethyl acetate.
3. The process according to claim 1 or 2, wherein in step 2), the concentration under reduced pressure and evaporation are carried out under water bath conditions of 30-40 ℃, preferably 30-35 ℃.
4. A process according to any one of claims 1 to 3, characterized in that, in step 3), the organic solvent E is dichloromethane, 1, 2-dichloroethane or chloroform, preferably dichloromethane;
preferably, the organic solvent F is methanol, ethanol or isopropanol, preferably methanol;
preferably, the volume ratio between the organic solvent E and the organic solvent F is 20: 1-30: 1, preferably 25: 1-30: 1.
5. the process according to any one of claims 1 to 4, wherein in step 1), the process for preparing the crude formoterol comprises the steps of:
i) formylating a compound shown in a formula V and anhydrous formic acid in the presence of a condensing agent and an organic solvent G, and crystallizing to obtain a compound shown in a formula VI;
Figure FDA0003382413110000021
ii) carrying out reduction reaction on the compound shown in the formula VI in the presence of a catalyst and an organic solvent H to obtain a formoterol crude product (formoterol reaction liquid);
Figure FDA0003382413110000022
preferably, in step i), the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2- (7-oxabenzotriazol) -N, N' -tetramethyluronium Hexafluorophosphate (HATU) or Dicyclohexylcarbodiimide (DCC), preferably EDCI;
preferably, in step i), the organic solvent G is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform and ethyl acetate, preferably dichloromethane or 1, 2-dichloroethane, more preferably dichloromethane;
preferably, in step ii), the catalyst is 5 w/w% to 10 w/w% palladium on carbon or Raney nickel, preferably 5 w/w% to 10 w/w% palladium on carbon, more preferably 10 w/w% palladium on carbon;
preferably, in step ii), the organic solvent H is a mixed solution of methanol and ethyl acetate, methanol, ethanol or tetrahydrofuran, and preferably a mixed solution of methanol and ethyl acetate.
6. The process according to claim 5, wherein in step i) the compound of formula V is prepared by:
I) carrying out salt forming reaction on the crude compound shown in the formula V and fumaric acid in an organic solvent A to prepare fumarate of the compound shown in the formula V;
II) carrying out a neutralization reaction on the fumarate of the compound shown in the formula V obtained in the step I) and alkali in an organic solvent B to obtain a purified compound shown in the formula V;
III) crystallizing the purified compound shown in the formula V obtained in the step II) in an organic solvent C to obtain a formoterol intermediate.
7. The process according to claim 6, characterized in that in step I), the organic solvent A is an ester and an alcohol, preferably ethyl acetate and an alcohol, more preferably ethyl acetate and a lower alkanol (e.g. methanol, ethanol);
preferably, in step I), the fumarate salt of the compound of formula v is prepared as follows:
heating the crude compound shown in the formula V and ethyl acetate to 60-75 ℃, adding fumaric acid and alcohol, stirring for dissolving, cooling to 20-35 ℃ after completely dissolving, stirring for 1-2h, continuously cooling to the internal temperature of-10-20 ℃, stirring for crystallizing for 1-2h to obtain the compound;
preferably, in step I), the fumarate salt of the compound of formula v is prepared as follows:
heating the crude compound shown in the formula V and ethyl acetate to 70-75 ℃, adding fumaric acid and alcohol, stirring for dissolving, cooling to 20-30 ℃ after completely dissolving, stirring for 1-2h, continuously cooling to the inner temperature of 0-10 ℃, stirring for crystallizing for 1-2h to obtain the compound;
preferably, in step I), the alcohol in the organic solvent a is selected from one or more of methanol, ethanol and isopropanol, preferably methanol or ethanol, more preferably methanol.
8. The process according to claim 6 or 7, wherein in step II) the purified compound of formula v is prepared as follows:
heating the fumarate of the compound shown in the formula V obtained in the step I) and alkali in an organic solvent B to the internal temperature of 20-40 ℃, and stirring for reacting for 4-6h to obtain the compound shown in the formula V;
preferably, in step II), the purified compound of formula v is prepared as follows:
heating the fumarate of the compound shown in the formula V obtained in the step I) and alkali in an organic solvent B to the internal temperature of 30-40 ℃, and stirring for reacting for 4-6h to obtain the compound shown in the formula V;
preferably, in step II), the organic solvent B is dichloromethane, ethyl acetate or acetonitrile, preferably dichloromethane or ethyl acetate, more preferably dichloromethane;
preferably, in step II), the base is a 10 w/v% -20 w/v% sodium carbonate solution or a 10 w/v% -20 w/v% potassium carbonate solution, preferably a 10 w/v% -20 w/v% sodium carbonate solution, more preferably a 10 w/v% sodium carbonate solution.
9. The process according to any one of claims 6 to 8, characterized in that in step III) the formoterol intermediate is prepared as follows:
heating the purified compound shown in the formula V) obtained in the step II) in an organic solvent C to 50-70 ℃, stirring for dissolving, slowly cooling to the internal temperature of 15-35 ℃ after completely dissolving, and stirring for crystallizing for 2-3h to obtain a formoterol intermediate;
preferably, in step III), the formoterol intermediate is prepared as follows:
heating the purified compound shown in the formula V obtained in the step II) in an organic solvent C to 60-70 ℃, stirring for dissolving, slowly cooling to the internal temperature of 20-30 ℃ after completely dissolving, and stirring for crystallizing for 2-3h to obtain a formoterol intermediate;
preferably, in step III), the organic solvent C is 50 v/v% ethanol, ethyl acetate or isopropyl ether, preferably 50 v/v% ethanol or isopropyl ether, more preferably isopropyl ether;
preferably, in step III), the ratio between the purified compound of formula v obtained in step II) and the solvent C is 1 g: 8.0mL-1 g: 15.0mL, preferably 1 g: 10.0mL-1 g: 12.0 mL.
10. A process for the preparation of formoterol fumarate (a compound of formula I) comprising the steps of:
carrying out salt reaction on a compound shown as a formula VII and fumaric acid in the presence of methanol, dimethyl sulfoxide (DMSO), an organic solvent I and water, and then crystallizing to obtain the compound;
Figure FDA0003382413110000041
preferably, the organic solvent I is acetone, dichloromethane, butanone, ethyl acetate or acetonitrile, preferably butanone, ethyl acetate or acetonitrile, most preferably butanone;
preferably, the compound of formula vii is prepared by a process according to any one of claims 1 to 9.
CN202111437905.1A 2018-11-28 2018-11-28 Preparation method of formoterol, medicinal salt and intermediate thereof Pending CN113999134A (en)

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