CN109535027A - A kind of preparation method of Formoterol, its officinal salt and its intermediate - Google Patents
A kind of preparation method of Formoterol, its officinal salt and its intermediate Download PDFInfo
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- CN109535027A CN109535027A CN201811434516.1A CN201811434516A CN109535027A CN 109535027 A CN109535027 A CN 109535027A CN 201811434516 A CN201811434516 A CN 201811434516A CN 109535027 A CN109535027 A CN 109535027A
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- 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
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- 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
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- 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
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- 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 present invention relates to the preparation methods of a kind of Formoterol, its officinal salt and its intermediate.The purification process of Formoterol intermediate (V compound represented of formula) of the invention includes the following steps: I) formula V compound represented crude product and fumaric acid salt-forming reaction occurs in organic solvent A, the fumarate of compound shown in formula V is made；II) making step I) neutralization reaction occurs in organic solvent B for the fumarate of compound shown in obtained formula V and alkali, V compound represented of formula of purifying is made；III) V compound represented of formula of the obtained purifying of step II) is crystallized in organic solvent C to get Formoterol intermediate
Description
Invention field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of Formoterol, its officinal salt and its intermediate
Preparation method.
Background technique
The chemical name of the officinal salt (formula Ι) of Formoterol are as follows: { N- [2- hydroxyl -5- [(RS) -1- hydroxyl -2-
[(RS) -2- (4- anisyl) -1- methylethylamino] ethyl] phenyl] formamide fumarate dihydrate, it is 2 sympathomimetic of β
Neural medicine, have it is long-acting, it is highly selective, the features such as stronger anti-inflammatory effect, rapid-action and slight side effect；With all quasi-
The typical basic structure of sympathetic nerve medicine, the substituent group on amino-type nitrogen make it have high selectivity to beta 2 receptor.Pharmacology is ground
Study carefully and show: FORMOTEROL FUMARATE DIHYDRATE is released by multiple links during inhibiting asthma pathology and inflammatory mediator
It puts, to play anti-inflammatory effect and inhibit the effect of pulmonary edema.Clinical research shows: oral or inhaled formoterol versus inhaled, can be effective
Control of asthma (especially Nocturnal) breaking-out, effect can maintain 12 hours or more.
The synthesis technology of Formoterol officinal salt (formula Ι) is extremely complex, US3994974, ES2005492 and WO2008/
The documents such as 035380A2 have been reported that.European Pharmacopoeia monograph in 2005 disclose Formoterol officinal salt (formula Ι) impurity and its
Limit is detailed in following table:
Synthetic route disclosed in US3994974 is as follows:
The method has the following shortcomings:
1) intermediate, final products and enantiomeric purity are not disclosed；
2) phase separates unwanted isomers (RS, SR) in post synthesis, and unwanted isomers not can be recycled, and cause into
This raising, pollution increase.
Synthetic route disclosed in ES2005492 is as follows:
This method has the disadvantage in that
1) belong to expensive rare substance using carcinogenic solvents such as harmful reagents and benzene such as hydrofluoric acid, crown ethers in synthesis process,
There are more serious health, environmental problem, be not suitable for being enlarged.
2) the undisclosed quality information about formoterol fumarate.
Synthetic route disclosed in WO2008/035380A2 is as follows:
By the study found that this method is applied to exist in the reaction for preparing Formoterol officinal salt (formula Ι) as follows asks
Topic:
1) it from starting material to formula in the preparation process of Ⅹ compound, needs repeatedly to purify, operate numerous by overnight grinding
It is trivial.In addition, adsorption effect of activated carbon in water is not significant in the preparation purification process of Ⅹ compound of formula, cause to crystallize crystallization difficulty, crystallization
Not exclusively, Ⅹ compound yield of formula is seriously affected.
2) slow using formic acid reaction speed in the preparation process of VI compound of formula, not exclusively, yield is inclined after purification for reaction
Low, using formic acid and acetic acid anhydride reactant, acetic anhydride can react the by-product (impurity C) for generating acetylation with V compound of formula, no
It easily removes, influences the purity and yield of VI compound of formula.
3) using repeatedly crystallization in the whole preparation process of final product formula Ι compound, hot conditions are cumbersome,
And formula Ι compound be heated at high temperature in a solvent be it is extremely unstable, especially in alcohols solvent, impurity A and miscellaneous can be generated
Matter F, purification effect is not significant, simultaneously amplifies production time poor controllability, and ideal purification effect is not achieved.
4) final product formula Ι is dried in vacuo at a temperature of 60 DEG C, and temperature is higher, there is the risk for losing the crystallization water.
To sum up, need to find a preferably method for preparation and purifying important intermediate V and VII compound of formula, so that
Its yield is higher, purity is higher, is suitable for industrialized production.
Summary of the invention
In order to overcome the defects of the prior art described above, the object of the present invention is to provide a kind of easy to operate, purity is high, yields
Height meets the purification process of a kind of Formoterol commercially produced, its officinal salt and its important intermediate.
Specifically, diastereoisomer can be removed it is an object of the present invention to provide V compound of purifying formula and efficiently
Improved method.
It is a further object to provide the improved methods of VI compound of formula preparation.
It is also another object of the present invention to provide the improved methods of VII compound of formula purifying.
A further object of the present invention is to provide the preparation method of formula Ι compound, wherein completing at salt and one step of purification, letter
Just efficiently.
Above-mentioned purpose of the invention adopts the following technical scheme that complete:
On the one hand, the present invention provides a kind of purification process of Formoterol intermediate (V compound represented of formula), the party
Method includes the following steps:
I) salt-forming reaction occurs in organic solvent A for V compound represented crude product of formula and fumaric acid, and V institute of formula is made
Show the fumarate of compound；
II) make step I) fumarate of compound shown in obtained formula V and alkali occur in organic solvent B in and it is anti-
It answers, V compound represented of formula of purifying is made；
III) V compound represented of formula of the obtained purifying of step II) is crystallized in organic solvent C to get Fu Mote
Sieve intermediate.
Preferably, in step I), the organic solvent A is ester and alcohol, preferably ethyl acetate and alcohol, more preferably second
Acetoacetic ester and low-grade alkane alcohol (such as methanol, ethyl alcohol).
Preferably, in step I), the fumarate of compound shown in the formula V the preparation method is as follows:
V compound represented crude product of formula and ethyl acetate are heated to 60-75 DEG C, add fumaric acid and alcohol, is stirred molten
Solution is cooled to 20-35 DEG C until completely dissolved, stirs 1-2h, continues to be down to -10-20 DEG C of Nei Wen, stirring and crystallizing 1-2h, i.e.,
?；
Preferably, in step I), the fumarate of compound shown in the formula V the preparation method is as follows:
V compound represented crude product of formula and ethyl acetate are heated to 70-75 DEG C, add fumaric acid and alcohol, is stirred molten
Solution is cooled to 20-30 DEG C until completely dissolved, stirs 1-2h, continues to be down to 0-10 DEG C of interior temperature, stirring and crystallizing 1-2h to get.
Preferably, in step I), alcohol in the organic solvent A be selected from one of methanol, ethyl alcohol and isopropanol or
It is a variety of, preferably methanol or ethyl alcohol, more preferably methanol.
Preferably, in step II), V compound represented of formula of the purifying the preparation method is as follows:
The fumarate of compound shown in formula V that step I) is obtained and alkali are heated to interior temperature 20- in organic solvent B
40 DEG C, be stirred to react 4-6h to get；
Preferably, in step II), V compound represented of formula of the purifying the preparation method is as follows:
The fumarate of compound shown in formula V that step I) is obtained and alkali are heated to interior temperature 30- in organic solvent B
40 DEG C, be stirred to react 4-6h to get.
Preferably, in step II), the organic solvent B is ethyl acetate, acetonitrile or methylene chloride, preferably dichloro
Methane or ethyl acetate, more preferably methylene chloride.
Preferably, in step II), the alkali is the sodium carbonate liquor or 10w/v%-20w/ of 10w/v%-20w/v%
The solution of potassium carbonate of v%, the preferably sodium carbonate liquor of 10w/v%-20w/v%, the more preferably sodium carbonate of 10w/v% are molten
Liquid.
Preferably, in step III), the Formoterol intermediate the preparation method is as follows:
V compound represented of formula of the obtained purifying of step II) is heated to 50-70 DEG C in organic solvent C, stirring
Dissolution, until completely dissolved, is slowly dropped to 15-35 DEG C of interior temperature, stirring and crystallizing 2-3h is to get Formoterol intermediate；
Preferably, in step III), the Formoterol intermediate the preparation method is as follows:
Step II) obtained V compound represented of formula of purifying is heated to 60-70 DEG C in organic solvent C, it stirs molten
Solution, until completely dissolved, is slowly dropped to 20-30 DEG C of interior temperature, stirring and crystallizing 2-3h is to get Formoterol intermediate.
Preferably, in step III), the organic solvent C is ethyl alcohol, ethyl acetate or the isopropyl ether of 50v/v%, excellent
It is selected as the ethyl alcohol or isopropyl ether of 50v/v%, more preferably isopropyl ether.
Preferably, in step III), the step II) obtained V compound represented of formula of purifying with it is described organic
Ratio between solvent C is 1g:8.0mL-1g:15.0mL, preferably 1g:10.0mL-1g:12.0mL.
Preferably, the preparation method of the V compound represented crude product of formula includes the following steps:
1) condensation reaction occurs for II compound represented of formula and III compound represented of formula, and chemical combination shown in formula IV is made
Object；
2) in the presence of reduced iron powder, ammonium chloride, dehydrated alcohol and water reduction reaction occurs for IV compound represented of formula,
V compound represented crude product of formula is made；
On the other hand, the present invention provides a kind of purification process of Formoterol (VII compound represented of formula), this method packet
Include following steps:
1) Formoterol crude product is extruded with nitrogen, filters, is washed with organic solvent D；
2) by the resulting filtrate decompression concentration and evaporation of step 1)；
3) organic solvent E and organic solvent F is added in the product obtained to step 2) evaporation, stirring is beaten to get good fortune not
Special sieve.
Preferably, in step 1), the organic solvent D is methanol and ethyl acetate mixture, methanol, ethyl alcohol or four
Hydrogen furans, preferably methanol and ethyl acetate mixture.
Preferably, in step 2), reduced pressure evaporation be under 30-40 DEG C of water bath condition, preferably 30 DEG C-
It is carried out under 35 DEG C of water bath condition.
Preferably, in step 3), the organic solvent E be methylene chloride, 1,2- dichloroethanes or chloroform, preferably two
Chloromethanes；
Preferably, in step 3), the organic solvent F is methanol, ethyl alcohol 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 Formoterol crude product includes the following steps:
I) V compound represented of formula, anhydrous formic acid in the presence of condensing agent and organic solvent G to that formylated occur anti-
It answers, crystallizes, VI compound represented of formula is made；
Ii) VI compound represented of formula in the presence of catalyst and organic solvent H to that reduction reaction occur to get Fu Mote
Sieve crude product (Formoterol reaction solution)；
Preferably, in step i), the condensing agent is 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride
(EDCI), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) or dicyclohexyl carbon two
Imines (DCC), preferably EDCI；
Preferably, in step i), the organic solvent G is selected from methylene chloride, 1,2- dichloroethanes, chloroform and acetic acid second
One of ester is a variety of, preferably methylene chloride or 1,2- dichloroethanes, more preferably methylene chloride；
Preferably, in step ii), the catalyst is the palladium charcoal or Raney's nickel of 5w/w%-10w/w%, preferably 5w/
The palladium charcoal of w%-10w/w%, the palladium charcoal of more preferably 10w/w%；
Preferably, in step ii), the organic solvent H be methanol and ethyl acetate mixture, methanol, ethyl alcohol or
Tetrahydrofuran, preferably methanol and ethyl acetate mixture.
Preferably, in step i), V compound represented of formula is prepared by purification process above-mentioned
Formoterol intermediate.
In another aspect, the present invention provides a kind of preparation side for preparing formoterol fumarate (Formulas I compound represented)
Method, this method comprises the following steps:
By VII compound represented of formula and fumaric acid in the presence of methanol, dimethyl sulfoxide (DMSO), organic solvent I and water
Occur salt-forming reaction, then crystallize to get.
Preferably, the organic solvent I is acetone, methylene chloride, butanone, ethyl acetate or acetonitrile, preferably butanone, second
Acetoacetic ester or acetonitrile, most preferably butanone.
Preferably, the Formoterol that VII compound represented of formula purification process above-mentioned is prepared.
In a specific embodiment, the preparation of preparation formoterol fumarate (Formulas I compound represented)
The reaction route of method is as follows:
Compared with prior art, preparation method route disclosed by the invention is short, simple and feasible, can substantially reduce and be produced into
This, is not related to danger or has the serious use for poisoning reagent, and be finally made high-purity (RR, SS >=99.8%, RS, SR≤
0.05%) target compound is suitble to industrialized production and application.
Detailed description of the invention
Hereinafter, carry out the embodiment that the present invention will be described in detail in conjunction with attached drawing, wherein
Fig. 1 is the 1H-NMR map of formoterol fumarate；
Fig. 2 is the HPLC map of impurity A and formoterol fumarate；
Fig. 3 is the HPLC map of impurity I and formoterol fumarate；
Fig. 4 is the system suitability map of impurity I and formoterol fumarate.
Specific embodiment
The embodiment of the present invention is described in detail below, but the present invention can be limited and be covered according to claim
Multitude of different ways implement.
Embodiment 1
1) reaction flask is added in II compound of formula (178.1g) and III compound of formula (161.7g), stirring is heated to interior temperature
90-100 DEG C, 2-3h is reacted, until 120-130 DEG C of interior temperature, reaction 2-3h is to (HPLC detection presses normalization method with peak area completely
Calculate, III compound of test sample Chinese style is less than 10%, i.e., it is believed that fully reacting), IV compound 320.5g of formula is obtained, is cooled to
After 70 ± 5 DEG C, dehydrated alcohol (220mL) dissolution is added, in case the next step.
2) reaction flask is added in IV compound of formula (220mL) of dehydrated alcohol dissolution and dehydrated alcohol (1280mL), stirred,
It is added reduced iron powder (199.7g), with dehydrated alcohol (1000mL) wash residual, ammonium chloride (191.3g) and water is added afterwards
(440mL) is heated to 75-85 DEG C of interior temperature, and reaction 2-3h is to (HPLC detection, is calculated with peak area by normalization method, for examination completely
IV compound of product Chinese style is less than 5.0%, i.e., it is believed that fully reacting), after be cooled to 75 ± 1 DEG C, ethyl acetate is added, stirs cold
But to 20-30 DEG C, afterwards be added ethyl acetate (550mL) washing, filtering, merge all filtrates, after by gained filtrate at 50-60 DEG C
Under the conditions of, drying is concentrated under reduced pressure, removes ethyl acetate and ethyl alcohol, ethyl acetate (1650mL) and water (1100mL) are added afterwards, stirs
It mixes, liquid separation removes water layer.Organic phase is washed 1 time with 10% aqueous sodium carbonate (1100mL), rear 20% sodium-chloride water solution
(1100mL) wash 1 time, then with anhydrous magnesium sulfate (220g) and active carbon (22g) stirring 1-2h, after be filtered to remove desiccant, use
Ethyl acetate (220mL) washs 3 times, and at a temperature of 50-60 DEG C, drying is concentrated under reduced pressure, and obtains bronzing and stick shape object to be formula V (A)
Compound 296g.Purity: 57.92%, diastereoisomer: 40.65%.
3) step a): being added reaction flask for formula V (A) compound (280g) and ethyl acetate (500mL), and stirring is dissolved,
It adds ethyl acetate (340mL), stirs, when being heated to 60~65 DEG C of interior temperature, fumaric acid (32.7g) and methanol is added
(210mL), until glutinous shape object is completely dissolved, after with 10 DEG C per hour of rate be cooled to 40 DEG C, rear water-bath is cooled to 20-30 DEG C,
1-2h is stirred, -10-0 DEG C of Nei Wen, stirring and crystallizing 1-2h is cooled to, solid is obtained by filtration, then is washed with ethyl acetate light to filtrate
Yellow, then at a temperature of 50 ± 5 DEG C, the very dry dry 4-6h of sky obtains light yellow solid 190g.
Step b): light yellow solid (130g), methylene chloride (650mL) and 10% sodium carbonate that step a) is obtained are water-soluble
Reaction flask is added in liquid (650mL), and being heated to 20-30 DEG C of interior temperature has bulk gas generation, stirs 4-6h, until solid completely disappears,
It stands, liquid separation, water layer is extracted 1 time with methylene chloride (325mL), is merged organic phase, is washed with 20% sodium-chloride water solution (650mL)
Organic phase is washed, is washed 2 times, then under the conditions of 40-50 DEG C, is concentrated under reduced pressure and removes solvent, obtain yellow oil 116g.
Step c): reaction flask is added in yellow oil (115g) that step b) is obtained and 50% ethyl alcohol (920mL), adds
For heat to 50-60 DEG C, stirring and dissolving is slowly dropped to 15-20 DEG C of interior temperature until completely dissolved, is maintained at 15-20 DEG C of condition of interior temperature
Under, solid is obtained by filtration in stirring and crystallizing 2-3h, solid is washed 3 times with 50% ethyl alcohol (115mL), then in 50 ± 5 DEG C of conditions
Lower vacuum drying 4-6h, obtain white solid be V compound 94.2g of formula, yield: 81.91%, purity: 99.91%, it is diastereomeric
Isomers: 0.04%.
4) by V compound of formula (65g) and 1, reaction flask is added in 2- dichloroethanes (300mL), in N2Under the conditions of by reaction solution
It is cooled to 0-10 DEG C, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDCI) (44.9g) and 1,2- is added afterwards
Anhydrous formic acid (12.0g) is slowly added dropwise inside under the conditions of 0-10 DEG C of temperature in dichloroethanes (25mL), after being added dropwise, keeps interior temperature
Under the conditions of 0-10 DEG C, 1-2h is reacted, until (HPLC detection, is calculated with peak area by normalization method, test sample Chinese style for fully reacting
V compound is less than 0.50%, i.e., it is believed that fully reacting.Cooling equipment is closed afterwards, and 10% aqueous sodium carbonate is added
(275mL) is warming up to 20-30 DEG C, stirs 0.5-1.0h, separates organic layer, and water layer is extracted with 1,2- dichloroethanes (275mL),
It is laminated simultaneously with 1,2- dichloroethanes afterwards, with 10% aqueous sodium carbonate (275mL) agitator treating 0.5-1.0h, then with 20% chlorine
Change sodium water solution (325mL) to wash 2 times, organic phase is concentrated under reduced pressure dry that the glutinous shape object of bronzing is formula VI under the conditions of 40-50 DEG C
Methanol 325mL is added in crude compound, heats 40-50 DEG C of stirring, after solid dissolution, is down to 0-10 DEG C, stirs 1-2h, mistake
Filter obtains solid, and 0-10 DEG C of methanol (65mL) of solid washs 2 times, then under the conditions of 45 ± 5 DEG C, is dried in vacuo 4-8h, obtains
To white solid be VI compound 56.2g of formula, yield: 81.84%, purity: 99.94%, non-corresponding isomers: 0.02%.
5) reaction flask is added in VI compound of formula (60g), 5% palladium charcoal (12.0g), tetrahydrofuran (720mL), unlatching is stirred
It mixes, leads into hydriding reactor and put nitrogen three times, reach 0.50~0.52MPa to pressure every time, then lead to hydrogen release gas three into hydriding reactor
Secondary, each pressure reaches 0.50~0.52MPa.Under the conditions of logical hydrogen is to 0.50~0.52MPa of pressure, it is heated to 30-35 DEG C,
Stirring 4~5h, (HPLC detection, is calculated with peak area by normalization method, impurity H < 1.0%, i.e., it is believed that reaction to fully reacting
Completely), then pressure is shed, is replaced once with 0.2~0.3MPa of nitrogen, reaction solution nitrogen is extruded, filtering, use tetrahydrofuran
Evaporation is concentrated under reduced pressure by filtrate under 30-35 DEG C of water bath condition in (300mL) washing reaction bottle and filter cake, and the time is less than 4h, very
Reciprocal of duty cycle is greater than -0.09MPa, adds methylene chloride (300mL), methanol (10mL) stirring, is beaten 3-4h under the conditions of 20-30 DEG C,
Solid is obtained by filtration, solid is washed 3 times with methylene chloride (60mL), under the conditions of 40 ± 5 DEG C, is dried in vacuo 4-6h, is obtained white
Color solid be VII compound 32.2g of formula, yield: 81.75%, purity: 99.93%, diastereoisomer: 0.02%, impurity A:
0.02%, impurity B, C, D, E, F, G, H are not detected.
6) reaction flask is added in VII compound of formula (25g), methanol (375mL) and dimethyl sulfoxide (DMSO) (50mL),
Under the conditions of 20-30 DEG C, fumaric acid (4.2g) and methanol (125mL) is added, stirring and dissolving stirs 10min after solid dissolution,
Water (50mL) and butanone (500mL) is added, is cooled to 0-10 DEG C, after having solid precipitation, under the conditions of 0-10 DEG C, stirs 2-
3h, filtering, solid are eluted 3 times with butanone (75mL), then under the conditions of 40 ± 5 DEG C, are dried in vacuo 4-6h, obtaining white solid is
Formula Ι compound 25.5g, yield: 83.68%, purity: 99.95%, diastereoisomer: 0.02%, impurity A: 0.01% (school
Positive divisor 1.75), impurity B, C, D, E, F, G, H are not detected.
The spectroscopic data of the formula Ι compound measured is 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 spectroscopic data prove formula Ιization
Conjunction object is formoterol fumarate, is detailed in Fig. 1.
Embodiment 2
1) V (A) compound (280g) is made in step 2) in embodiment 1 and reaction flask is added in ethyl acetate (500mL),
Stirring, dissolution, add ethyl acetate (340mL), stir, when being heated to 65~70 DEG C of interior temperature, be added fumaric acid (32.7g) and
Ethyl alcohol (210mL), until glutinous shape object is completely dissolved, after with 10 DEG C per hour of rate be cooled to 40 DEG C, rear water-bath is cooled to 30-35
DEG C, 1-2h is stirred, is cooled to 0-10 DEG C of interior temperature, stirring and crystallizing 1-2h is obtained by filtration solid, then is washed with ethyl acetate to filtrate
It is faint yellow, then at a temperature of 50 ± 5 DEG C, the very dry dry 4-6h of sky obtains light yellow solid 190g.
Light yellow solid (130g), ethyl acetate (650mL) and 15% aqueous sodium carbonate (650mL) that upper step is obtained
Reaction flask is added, being heated to 30-40 DEG C of interior temperature has bulk gas generation, stirs 4-6h, until solid completely disappears, stand, liquid separation,
Aqueous layer with ethyl acetate (325mL) extracts 1 time, merges organic phase, washs organic phase with 20% sodium-chloride water solution (650mL),
Washing 2 times, then under the conditions of 40-50 DEG C, be concentrated under reduced pressure and remove solvent, obtain yellow oil 116g.
Reaction flask is added in the yellow oil (115g) and ethyl acetate (1150mL) that upper step is obtained, and is heated to 60-70
DEG C, stirring and dissolving is slowly dropped to 20-25 DEG C of interior temperature until completely dissolved, is maintained under the conditions of 20-25 DEG C of interior temperature, stirring and crystallizing
Solid is obtained by filtration in 2-3h, solid is washed 3 times with ethyl acetate (115mL), then be dried in vacuo 4- under the conditions of 50 ± 5 DEG C
6h, obtain white solid be V compound 94.8g of formula, yield: 82.43%, purity: 99.82%, diastereoisomer:
0.02%.
2) reaction flask is added in V compound of formula (65g) and chloroform (300mL), in N2Under the conditions of reaction solution is cooled to 0-
10 DEG C, 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) (89.1g) and chlorine are added afterwards
Anhydrous formic acid (12.0g) is slowly added dropwise inside under the conditions of 0-10 DEG C of temperature in imitative (25mL), after being added dropwise, keeps interior temperature in 0-10
Under the conditions of DEG C, 1-2h is reacted, until (HPLC detection, is calculated with peak area by normalization method, V chemical combination of test sample Chinese style for fully reacting
Object is less than 0.50%, i.e., it is believed that fully reacting.Cooling equipment is closed afterwards, is added 10% aqueous sodium carbonate (275mL), heating
To 20-30 DEG C, 0.5-1.0h is stirred, separates organic layer, water layer is extracted with chloroform (275mL), merged afterwards with chloroform layer, with 10%
Aqueous sodium carbonate (275mL) agitator treating 0.5-1.0h, then washed 2 times with 20% sodium-chloride water solution (325mL), it is organic
Mutually under the conditions of 40-50 DEG C, reduced pressure is dry that bronzing sticks shape object as VI crude compound of formula, and methanol 325mL is added, heats
40-50 DEG C of stirring is down to 0-10 DEG C after solid dissolution, stirs 1-2h, is obtained by filtration solid, 0-10 DEG C of methanol of solid
(65mL) is washed 2 times, then under the conditions of 45 ± 5 DEG C, is dried in vacuo 4-8h, and obtaining white solid is VI compound 56.6g of formula,
Yield is 82.42%, purity 99.86%, non-corresponding isomers 0.05%.
3) by VI compound of formula (60g), 10% palladium charcoal (12.0g), methanol and (360mL) and ethyl acetate (360mL) plus
Enter reaction flask, open stirring, lead into hydriding reactor and put nitrogen three times, reach 0.50~0.52MPa to pressure every time, then to hydrogenation
Lead to hydrogen release gas three times in kettle, each pressure reaches 0.50~0.52MPa.Under the conditions of logical hydrogen is to 0.50~0.52MPa of pressure,
It is heated to 30-35 DEG C, (HPLC detection, is calculated with peak area by normalization method, impurity H < 4~5h of stirring to fully reacting
1.0%, i.e., it is believed that fully reacting), then pressure is shed, it is replaced with 0.2~0.3MPa of nitrogen once, by reaction solution nitrogen pressure
Out, it filters, with methanol (150mL) and ethyl acetate (150mL) mixed solution washing reaction bottle and filter cake, by filtrate in 35-40
Under DEG C water bath condition, evaporation is concentrated under reduced pressure, the time is less than 4h, and vacuum degree is greater than -0.09MPa, adds 1,2- dichloroethanes
(300mL), methanol (12mL) stir, and are beaten 3-4h under the conditions of 20-30 DEG C, solid, solid 1,2- dichloroethanes is obtained by filtration
(60mL) is washed 3 times, under the conditions of 40 ± 50 DEG C, is dried in vacuo 4-6h, and obtaining white solid is VII compound 32.5g of formula, is received
Rate: 82.52%, purity: 99.89%, diastereoisomer: 0.05%, impurity A: 0.02%, impurity B, C, D, E, F, G, H are equal
It is not detected.
Embodiment 3
1) reaction flask is added in V compound of high-purity formula (65g) and ethyl acetate (300mL), in N2Under the conditions of will reaction
Liquid is cooled to 0-10 DEG C, dicyclohexylcarbodiimide (DCC) (62.3g) and ethyl acetate (25mL) is added afterwards, inside temperature 0-10
Under the conditions of DEG C, anhydrous formic acid (12.0g) is slowly added dropwise, after being added dropwise, keeps interior temperature under the conditions of 0-10 DEG C, reacts 1-2h,
To fully reacting, (HPLC detection, is calculated with peak area by normalization method, V compound of test sample Chinese style is less than 0.50%
Think fully reacting.), it is rear to close cooling equipment, it is added 10% aqueous sodium carbonate (275mL), is warming up to 20-30 DEG C, stirring
0.5-1.0h, separates organic layer, and aqueous layer with ethyl acetate (275mL) extracts, merges afterwards with ethyl acetate layer, with 10% sodium carbonate
Aqueous solution (275mL) agitator treating 0.5-1.0h, then washed 2 times with 20% sodium-chloride water solution (325mL), organic phase exists
Under the conditions of 40-50 DEG C, reduced pressure is dry that bronzing sticks shape object as VI crude compound of formula, and methanol 325mL, heating 40- is added
50 DEG C of stirrings are down to 0-10 DEG C after solid dissolution, stir 1-2h, are obtained by filtration solid, 0-10 DEG C of methanol of solid
(65mL) is washed 2 times, then under the conditions of 45 ± 5 DEG C, is dried in vacuo 4-8h, and obtaining white solid is VI compound 55.99g of formula,
Yield: 81.53%, purity: 99.91%, non-corresponding isomers: 0.04%.
2) reaction flask is added in VI compound of formula (60g), Raney's nickel (12.0g), tetrahydrofuran (720mL), opens stirring,
Lead into hydriding reactor and put nitrogen three times, reach 0.50~0.52MPa to pressure every time, then leads to hydrogen release gas three times into hydriding reactor,
Each pressure reaches 0.50~0.52MPa.Under the conditions of logical hydrogen is to 0.50~0.52MPa of pressure, it is heated to 30-35 DEG C, is stirred
Mixing 4~5h, (HPLC detection, is calculated with peak area by normalization method, impurity H < 1.0%, i.e., it is believed that having reacted to fully reacting
Entirely), then pressure is shed, is replaced once with 0.2~0.3MPa of nitrogen, reaction solution nitrogen is extruded, filtering, use tetrahydrofuran
Evaporation is concentrated under reduced pressure by filtrate under 35 DEG C of water bath conditions in (300mL) washing reaction bottle and filter cake, and the time is less than 4h, vacuum degree
Greater than -0.09MPa, chloroform (300mL), methanol (12mL) stirring are added, 3-4h is beaten under the conditions of 20-30 DEG C, is obtained by filtration
Solid, solid are washed 3 times with chloroform (60mL), under the conditions of 40 ± 5 DEG C, are dried in vacuo 4-6h, and obtaining white solid is formula VII
Compound 32.1g, yield: 81.50%, purity: 99.91%, diastereoisomer: 0.03%, impurity A: 0.02%, impurity B,
C, D, E, F, G, H are not detected.
Embodiment 4
1) reaction is added in formula V (A) compound (280g) made from step 2) in embodiment 1 and ethyl acetate (500mL)
Bottle, stirring, dissolution, adds ethyl acetate (340mL), stirs, and when being heated to 70~75 DEG C of interior temperature, fumaric acid is added
(32.7g) and ethyl alcohol (210mL), until glutinous shape object is completely dissolved, after with 10 DEG C per hour of rate be cooled to 40 DEG C, rear water-bath drop
Temperature stirs 1-2h, is cooled to 10-20 DEG C of interior temperature, stirring and crystallizing 1-2h is obtained by filtration solid, then uses ethyl acetate to 20-30 DEG C
Washing is faint yellow to filtrate, then at a temperature of 50 ± 5 DEG C, the very dry dry 4-6h of sky obtains light yellow solid 190g.
2) light yellow solid (130g), acetonitrile (650mL) and 20% wet chemical (650mL) obtained upper step adds
Enter reaction flask, being heated to 30-40 DEG C of interior temperature has bulk gas generation, stirs 4-6h, until solid completely disappears, stands, liquid separation, water
Layer is extracted 1 time with acetonitrile (325mL), merges organic phase, washs organic phase, washing 2 with 20% sodium-chloride water solution (650mL)
It is secondary, then under the conditions of 40-50 DEG C, be concentrated under reduced pressure and remove solvent, obtaining yellow oil is 116g.
3) reaction flask is added in the yellow oil (115g) and isopropyl ether (1380mL) obtained upper step, is heated to 60-70
DEG C, stirring and dissolving is slowly dropped to 25-30 DEG C of interior temperature until completely dissolved, is maintained under the conditions of 25-30 DEG C of interior temperature, stirring and crystallizing
Solid is obtained by filtration in 2-3h, solid is washed 3 times with isopropyl ether (115mL), then be dried in vacuo 4-6h under the conditions of 50 ± 5 DEG C,
Obtain white solid be V compound 93.8g of formula, yield: 81.57%, purity: 99.89%, diastereoisomer: 0.03%.
Embodiment 5
VI compound of formula (60g), 10% palladium charcoal (12.0g), ethyl alcohol (720mL) is made in step 4) in embodiment 1 to be added
Reaction flask opens stirring, leads into hydriding reactor and puts nitrogen three times, reaches 0.50~0.52MPa to pressure every time, then to hydriding reactor
In lead to hydrogen release gas three times, each pressure reaches 0.50~0.52MPa.Under the conditions of logical hydrogen is to 0.50~0.52MPa of pressure, add
Heat to 30-35 DEG C, stirring 4~5h to fully reacting (HPLC detection, with peak area by normalization method calculating, impurity H < 1.0%,
I.e. it is believed that fully reacting), then pressure is shed, it is replaced once, reaction solution nitrogen is extruded, mistake with 0.2~0.3MPa of nitrogen
Evaporation, time is concentrated under reduced pressure by filtrate under 30-35 DEG C of water bath condition with ethyl alcohol (300mL) washing reaction bottle and filter cake in filter
Less than 4h, vacuum degree is greater than -0.09MPa, adds methylene chloride (300mL), methanol (15mL) stirring, under the conditions of 20-30 DEG C
It is beaten 3-4h, solid is obtained by filtration, solid is washed 3 times with methylene chloride (60mL), under the conditions of 40 ± 5 DEG C, is dried in vacuo 4-
6h, obtain white solid be VII compound 32.0g of formula, yield: 81.25%, purity: 99.92%, diastereoisomer:
0.02%, impurity A: 0.02%, impurity B, C, D, E, F, G, H are not detected.
Embodiment 6
1) reaction flask is added in II compound of formula (1424.8g) and III compound of formula (1336.8g), stirring is heated to interior
Warm 90-100 DEG C, 2-3h is reacted, until 120-130 DEG C of interior temperature, reaction 2-3h to (HPLC detection, with peak area by normalization completely
Method calculates, and III compound of test sample Chinese style is less than 10%, i.e., it is believed that fully reacting.), IV compound 2480.2g of formula is obtained, it is cold
But to dehydrated alcohol (1760mL) dissolution after 70 ± 5 DEG C, is added, in case the next step.
2) reaction flask is added in IV compound of formula (1760mL) of dehydrated alcohol dissolution and dehydrated alcohol (10240mL), stirred
It mixes, is added reduced iron powder (1597.6g), with dehydrated alcohol (8000mL) wash residual, ammonium chloride (1530.4g) and water are added afterwards
(3520mL) is heated to 75-85 DEG C of interior temperature, and reaction 2-3h is to (HPLC detection, is calculated with peak area by normalization method, is supplied completely
IV compound of test product Chinese style is less than 5.0%, i.e., it is believed that fully reacting.) after be cooled to 75 ± 1 DEG C, ethyl acetate, stirring is added
Be cooled to 20-30 DEG C, afterwards be added ethyl acetate (4400mL) washing, filtering, merge all filtrates, after by gained filtrate in 50-
Under the conditions of 60 DEG C, drying is concentrated under reduced pressure, removes ethyl acetate and ethyl alcohol, ethyl acetate (13200mL) and water are added afterwards
(8800mL), stirring, liquid separation remove water layer.Organic phase is washed 1 time with 10% aqueous sodium carbonate (8800mL), rear 20% chlorine
Change sodium water solution (8800mL) to wash 1 time, then stirs 1-2h with anhydrous magnesium sulfate (1760g) and active carbon (176g), it is rear to filter
Desiccant is removed, is washed 3 times with ethyl acetate (1760mL), at a temperature of 50-60 DEG C, drying is concentrated under reduced pressure, obtains bronzing
Glutinous shape object is (A) compound of formula V 2350.5g.Purity: 59.92%, diastereoisomer: 32.65%.
3) reaction flask is added in formula V (A) compound (2240g) and ethyl acetate (4000mL), stirring, dissolution add
When being heated to 70~75 DEG C of interior temperature, fumaric acid (261.6g) and isopropanol is added in ethyl acetate (2720mL), stirring
(1680mL), until glutinous shape object is completely dissolved, after with 10 DEG C per hour of rate be cooled to 40 DEG C, rear water-bath is cooled to 20-30 DEG C,
1-2h is stirred, 0-10 DEG C of interior temperature is cooled to, solid is obtained by filtration in stirring and crystallizing 1-2h, then is washed with ethyl acetate light to filtrate
Yellow, then at a temperature of 50 ± 5 DEG C, the very dry dry 4-6h of sky obtains light yellow solid 1480.1g.
Light yellow solid (1040g), methylene chloride (5200mL) and 10% wet chemical that upper step is obtained
Reaction flask is added in (5200mL), and being heated to 30-40 DEG C of interior temperature has bulk gas generation, stirs 4-6h, until solid completely disappears, it is quiet
It sets, liquid separation, water layer is extracted 1 time with methylene chloride (2600mL), is merged organic phase, is washed with 20% sodium-chloride water solution (5200mL)
Organic phase is washed, is washed 2 times, then under the conditions of 40-50 DEG C, is concentrated under reduced pressure and removes solvent, obtain yellow oil 928.6g.
Reaction flask is added in the yellow oil (920g) and isopropyl ether (13800mL) that upper step is obtained, and is heated to 60-70
DEG C, stirring and dissolving is slowly dropped to 30-35 DEG C of interior temperature until completely dissolved, is maintained under the conditions of 30-35 DEG C of interior temperature, stirring and crystallizing
Solid is obtained by filtration in 2-3h, solid is washed 3 times with isopropyl ether (920mL), then be dried in vacuo 4-6h under the conditions of 50 ± 5 DEG C,
Obtain white solid be V compound 710.4g of formula, yield: 77.17%, purity: 99.90%, diastereoisomer: 0.04%.
4) reaction flask is added in V compound of formula (520g) and methylene chloride (2400mL), in N2Under the conditions of will react liquid cooling
But to 0-10 DEG C, 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) are added afterwards
(359.2g) and methylene chloride (200mL) is slowly added dropwise anhydrous formic acid (96.0g), is added dropwise inside under the conditions of 0-10 DEG C of temperature
Afterwards, temperature reacts 1-2h under the conditions of 0-10 DEG C in keeping, until reflection (HPLC detection, by peak area based on normalization method completely
It calculates, V compound of test sample Chinese style is less than 0.50%, i.e., it is believed that fully reacting.), it is rear to close cooling equipment, 10% carbon is added
Acid sodium aqueous solution (2200mL) is warming up to 20-30 DEG C, stirs 0.5-1.0h, separates organic layer, water layer methylene chloride
(2200mL) is extracted, and is merged afterwards with dichloromethane layer, with 10% aqueous sodium carbonate (2200mL) agitator treating 0.5-1.0h, then
It is washed 2 times with 20% sodium-chloride water solution (2600mL), organic phase is concentrated under reduced pressure reddish brownly drying under the conditions of 40-50 DEG C
It is VI crude compound of formula that color, which sticks shape object, is added methanol (2600mL), and 40-50 DEG C of stirring is heated, and after solid dissolution, is down to 0-
10 DEG C, 1-2h is stirred, solid is obtained by filtration, 0-10 DEG C of methanol (520mL) of solid washs 2 times, then in 45 ± 5 DEG C of conditions
Under, it is dried in vacuo 4-8h, obtaining white solid is VI compound 446.3g of formula, yield: 81.25%.Purity: 99.91%, it is non-right
Answer isomers: 0.02%.
5) VI compound of formula (480g), 10% palladium charcoal (96.0g), methanol (2880mL) and ethyl acetate (2880mL) are added
Enter reaction flask, open stirring, lead into hydriding reactor and put nitrogen three times, reach 0.50~0.52MPa to pressure every time, then to hydrogenation
Lead to hydrogen release gas three times in kettle, each pressure reaches 0.50~0.52MPa.Under the conditions of logical hydrogen is to 0.50~0.52MPa of pressure,
It is heated to 30-35 DEG C, (HPLC detection, is calculated with peak area by normalization method, impurity H < 4~5h of stirring to fully reacting
1.0%, i.e., it is believed that fully reacting), then pressure is shed, it is replaced with 0.2~0.3MPa of nitrogen once, by reaction solution nitrogen pressure
Out, it filters, with methanol (1200mL) and ethyl acetate (1200mL) mixed solution washing reaction bottle and filter cake, by filtrate in 30-
Under 35 DEG C of water bath conditions, evaporation is concentrated under reduced pressure, the time is less than 4h, and vacuum degree is greater than -0.09MPa, adds 1,2- dichloroethanes
(2400mL), ethyl alcohol (96mL) stir, and are beaten 3-4h under the conditions of 20-30 DEG C, solid, solid methylene chloride is obtained by filtration
(480mL) is washed 3 times, under the conditions of 40 ± 5 DEG C, is dried in vacuo 4-6h, and obtaining white solid is VII compound 269.4g of formula, is received
Rate: 85.51%, purity: 99.92%, diastereoisomer: 0.03%, impurity A: 0.02%, impurity B, C, D, E, F, G, H are equal
It is not detected.
6) reaction flask is added in VII compound of formula (200g), methanol (3000mL) and dimethyl sulfoxide (DMSO) (400mL),
Under the conditions of 20-30 DEG C, fumaric acid (33.6g) and methanol (1000mL) is added, stirring and dissolving stirs after solid dissolution
10min is added water (400mL) and ethyl acetate (4000mL), is cooled to 0-10 DEG C, after having solid precipitation, in 0-10 DEG C of item
Under part, 2-3h, filtering are stirred, solid is eluted 3 times with butanone (600mL), then under the conditions of 40 ± 5 DEG C, is dried in vacuo 4-6h, is obtained
To white solid be formula Ι compound 210.8g, yield: 86.32%, purity: 99.93%, diastereoisomer (impurity I):
0.02%, impurity A: 0.02%, impurity B, C, D, E, F, G, H are not detected.
High performance liquid chromatography detection is carried out to the formoterol fumarate that embodiment 6 is prepared.High performance chromatograph,
Agilent1260 Ι detector VWD, chromatographic column Agilent zorbax SB-C8,150*4.6mm, 5 μm；With phosphate buffer
(take biphosphate sodium-hydrate 3.73g, water 1000ml added to make to dissolve, add phosphorus acid for adjusting pH value to 3.3) be mobile phase A, second
Nitrile is Mobile phase B, carries out gradient elution, and actual conditions are as follows:
| Time (min) | Mobile phase A | Mobile phase B (%) |
| 0 | 84 | 16 |
| 10 | 84 | 16 |
| 37 | 30 | 70 |
| 40 | 84 | 16 |
| 55 | 84 | 16 |
Detection wavelength is 214nm；Flow velocity: 1.0mL/min；Column temperature is 30 DEG C, is detailed in Fig. 2, testing result see the table below 1:
The HPLC atlas analysis of 1 impurity A of table and formoterol fumarate
High performance liquid chromatography detection is carried out to the formoterol fumarate that embodiment 6 is prepared.High performance chromatograph,
Agilent1260 Ι detector VWD, chromatographic column Shodex Asahipak ODP-50 4D, 150*4.6mm, 5 μm；With acetonitrile: sulphur
Sour potassium buffer (12:88) is mobile phase；Detection wavelength is 225nm；Flow velocity: 0.5mL/min；Column temperature is 30 DEG C, is detailed in Fig. 3；
System suitability data are detailed in Fig. 4；Testing result see the table below 2:
The HPLC atlas analysis of table 2 impurity I and formoterol fumarate
The formoterol fumarate being prepared in embodiment 6 is accelerated, long-time stability are investigated.Acceleration for stabilization
Property: test drug stability test case (immortal SHH-5005D), placement condition: 40 DEG C ± 2 DEG C, 75% ± 5%RH；It is long-term steady
It is qualitative: test drug stability test case (immortal SHH-5005D), placement condition: 25 DEG C ± 2 DEG C, 60% ± 5%RH, as a result
It is detailed in the following table 3 and 4.
3 accelerated stability data statistic of table
Conclusion: formoterol fumarate highly finished product sample it is accelerated test 6 months, character, moisture, specific rotation, fusing point,
Significant change did not occurred compared with sample with 0 month in relation to substance, content, isomers, meets the requirements.
4 long-term stable experiment tables of data of table
Conclusion: formoterol fumarate highly finished product sample moisture, specific rotation, was melted through long term test 12 months, character
Compared with sample significant change did not occurred for point with 0 month in relation to substance, content, isomers, met the requirements.
Comparative example 1
It is tested referring to embodiment 1, difference is only that step 3) step a): fumaric acid (32.7g) and ethylene glycol is added
(210mL), until glutinous shape object is completely dissolved, V compound yield of formula finally obtained: 85.03%, purity: 98.32%, it is diastereomeric
Isomers: 0.10%.
To find out from the present embodiment, organic solvent A uses ethylene glycol, although obtained V compound yield of formula is higher,
Purity is relatively low, diastereoisomer poor removal effect.
Comparative example 2
It is tested referring to embodiment 1, difference is only that 3) step a): continuing to be down to Nei Wen -20 to -10 DEG C, stirring analysis
Brilliant 1-2h, V compound yield of formula finally obtained: 82.14%, purity: 98.91%, diastereoisomer: 0.09%.
It is tested referring to embodiment 1, difference is only that 3) step a): continuing to be down to 20 to 30 DEG C of interior temperature, stirring and crystallizing
1-2h, V compound yield of formula finally obtained: 79.22%, purity: 99.92%, diastereoisomer: 0.04%.
Find out from the present embodiment, for crystallization temperature at -20 to -10 DEG C, obtained V compound purity of formula is poor, isomers removal
Effect is bad, and for crystallization temperature at 20 to 30 DEG C, obtained V compound yield of formula is lower.
Comparative example 3
It is tested referring to embodiment 1, difference is only that step 3) step c): the yellow oil that step b) is obtained
Reaction flask is added in (115g) and acetonitrile (920mL), V compound yield of formula finally obtained: 85.27%, purity: and 97.88%,
Diastereoisomer: 0.15%.
Finding out from the present embodiment, organic solvent C uses acetonitrile, although obtained obtained V compound yield of formula is very high,
But purity is low, diastereoisomer poor removal effect.
Comparative example 4
It is tested referring to embodiment 1, difference is only that reaction solution nitrogen is extruded, filtered by step 5), uses methanol
(150mL) and ethyl acetate (150mL) mixed solution washing reaction bottle and filter cake subtract by filtrate under 40-50 DEG C of water bath condition
Concentration and evaporation is pressed, obtains VII compound yield of formula: 81.11%, purity: 99.15%, diastereoisomer: 0.02%, impurity A:
0.12%, impurity F: 0.10%, impurity B, C, D, E, G, H are not detected.
Find out from the present embodiment, for thickening temperature at 40-50 DEG C, VII compound impurities of formula are obviously higher.
Comparative example 5
It is tested referring to embodiment 1, difference is only that step 5) under 30-35 DEG C of water bath condition, depressurizes filtrate dense
Contracting evaporation, time are less than 4h, and vacuum degree is greater than -0.09MPa, add n-hexane (300mL), methanol (10mL) stirring, mashing
Solid is obtained by filtration in 3-4h, and solid is washed 3 times with n-hexane (60mL), obtains VII compound yield of formula: 85.56%, purity:
98.00%, diastereoisomer: 0.03%, impurity A: 0.11%, impurity F: 0.09%, impurity B, C, D, E, G, H are not examined
Out.
Find out from the present embodiment, organic solvent D uses n-hexane, and VII compound yield of formula is high, and purity is small, and impurity is higher.
Comparative example 6
It is tested referring to embodiment 1, difference is only that step 5) under 30-35 DEG C of water bath condition, depressurizes filtrate dense
Contracting evaporation, time are less than 4h, and vacuum degree is greater than -0.09MPa, adds methylene chloride (300mL), ethyl acetate (10mL) stirs
It mixes, is beaten 3-4h, solid is obtained by filtration, solid is washed 3 times with methylene chloride (60mL), obtain VII compound yield of formula:
70.99%, purity: 99.94%, diastereoisomer: 0.02%, impurity A: 0.02%, impurity B, C, D, E, F, G, H are not examined
Out.
Find out from the present embodiment, organic solvent F uses ethyl acetate, and VII compound yield of formula is relatively low.
Comparative example 7
It is tested referring to embodiment 1, difference is only that step 5) adds n-hexane (300mL), methanol (10mL) stirs
It mixes, is beaten 3-4h, solid is obtained by filtration, solid is washed 3 times with n-hexane (60mL), obtain VII compound yield of formula:
85.77%, purity: 98.33%, diastereoisomer: 0.03%, impurity A: 0.13%, impurity F: 0.08%, impurity B, C, D,
E, G, H are not detected.
Find out from the present embodiment, when solvent E uses n-hexane, VII compound purity of formula is low, and impurity is higher.
Comparative example 8
It is tested referring to embodiment 1, difference is only that step 5) adds methylene chloride (300mL), dimethyl sulfoxide
(10mL) stirring, is beaten 3-4h, solid is obtained by filtration, and solid is washed 3 times with methylene chloride (60mL), obtains VII compound of formula receipts
Rate: 72.12%, purity: 99.91%, diastereoisomer: 0.03%, impurity A: 0.03%, impurity B, C, D, E, F, G, H are equal
It is not detected.
Find out from the present embodiment, when solvent F uses dimethyl sulfoxide, VII compound yield of formula is relatively low.
Comparative example 9
Reaction flask is added in formula V (A) compound (250g) and isopropyl ether (2000mL) that step 2) in embodiment 1 is obtained,
It is heated to 50-60 DEG C, stirring and dissolving is slowly dropped to 20-30 DEG C of interior temperature until completely dissolved, is maintained at 20-30 DEG C of condition of interior temperature
Under, solid is not precipitated yet after stirring 2-3h, just has solid precipitation after stirring 20h, solid is obtained by filtration, by solid isopropyl ether
(250mL) is washed 3 times, then is dried in vacuo 4-6h under the conditions of 50 ± 5 DEG C, and obtaining white solid is V compound 32g of formula, yield
It is relatively low, purity 97.6%, non-corresponding isomers: 0.05%.
Find out from the present embodiment, obtains Formula V (A) compound without at salt, free directly to be crystallized with isopropyl ether, product is difficult
Crystallization, and purity is low.
Comparative example 10
VI compound of formula (60g) that step 4) in embodiment 1 is obtained, 10% palladium charcoal (12.0g), methanol (360mL) and
Reaction flask is added in ethyl acetate (360mL), opens stirring, leads into hydriding reactor and puts nitrogen three times, reaches 0.50 to pressure every time
~0.52MPa, then lead to hydrogen release gas three times into hydriding reactor, each pressure reaches 0.50~0.52MPa.In logical hydrogen to pressure
Under the conditions of 0.50~0.52MPa, it is heated to 30-35 DEG C, (HPLC detection presses normalizing with peak area to 4~5h of stirring to fully reacting
Change method calculates, impurity H < 1.0%, i.e., it is believed that fully reacting), then pressure is shed, it is replaced once with 0.2~0.3MPa of nitrogen,
Reaction solution nitrogen is extruded, filtering, with methanol (150mL) and ethyl acetate (150mL) mixed solution washing reaction bottle and filter
Evaporation is concentrated under reduced pressure by filtrate under 30-35 DEG C of water bath condition in cake, and the time is less than 4h, and vacuum degree is greater than -0.09MPa, solvent
After concentration is dry, it is directly added into methanol (600mL) and reaction flask is added in dimethyl sulfoxide (DMSO) (80mL), in 20-30 DEG C of condition
Under, fumaric acid (6.7g) and methanol (200mL) is added, stirring and dissolving stirs 10min after solid dissolution, is added water (80mL)
With butanone (800mL), it is cooled to 0-10 DEG C, after having solid precipitation, under the conditions of 0-10 DEG C, stirs 2-3h, filtering, solid is used
Butanone (180mL) elutes 3 times, then under the conditions of 40 ± 5 DEG C, is dried in vacuo 4-6h, and obtaining white solid is formula Ι compound
27.6g, yield: 70.35%, purity: 98.33%, diastereoisomer (impurity I): 0.02%, impurity A: 0.28%, impurity
F:0.21%, impurity B, C, D, E, G, H are not detected.
Find out from the present embodiment, the post-processing of preparation formula Ι compound has been concentrated, without purifying the formula Ι obtained directly at salt
Compound purity is low, and impurity is higher.
Comparative example 11
Formoterol fumarate is prepared according to method disclosed in WO2008/035380A2 in background technique, specific as follows:
1) 2- { benzyl-[2- (4- methoxyphenyl) -1- Methylethyl] amino } -1- (4- benzyloxy -3- nitrobenzophenone) -
The preparation of ethyl alcohol (formula IV)
Into 5L four-hole boiling flask be added 188g (0.358mol) 2- benzyl -2-4- methoxyphenyl) -1- methyl second
Base] amino } -1- (4- benzyloxy -3- nitrobenzophenone)-ethyl ketone (X) and 2.5L methanol.Under RT (25-30 DEG C), to the anti-of stirring
It answers in liquid, the total 35g of 10 equal parts (0.921mol) sodium borohydride is added.After addition, acquired solution is stirred overnight at 25-30 DEG C.
After rotating methanol, gained residue is dissolved in toluene (2.0L) and is washed with water (2.5L).Then toluene solution is lived
Property charcoal is stirred and is filtered.It is concentrated under reduced pressure, removes toluene, obtaining yellow oil is IV compound 205g of formula.HPLC purity: RR and
SS isomers: 50.21%；RS and SR isomers: 44.43%.
The purifying of IV compound of formula:
Be added into 2L four-hole boiling flask above-mentioned oily compound object (205g) and under room temperature (25-30 DEG C) with isopropyl ether
(1200mL) grinding is stayed overnight together.Yellow solid (110g) is obtained by filtration.The solid chemical compound is again with different under the conditions of 25-30 DEG C
Propyl ether (650mL) recrystallization is further purified, and obtaining yellow crystal object is IV compound 80g of formula.HPLC purity: RR and SS isomery
Body: > 96.46%；RS and SR isomers: < 3.54%.
2) 1- (3- amino -4- benzyloxy-phenyl) -2- { benzyl-[2- (4- methoxyphenyl) -1- Methylethyl] amino }
The preparation of ethyl alcohol (V)
The nitroalcohol derivative (15g) and methanol (500mL) of formula IV are added into 2L stainless steel hydrogenation reaction cauldron, uses nitrogen
Raney's nickel catalyst (3-5g) (being washed in advance with methanol) is added into the solution in protection.Then pass to hydrogen and in 40-
60psi H2It is hydrogenated under pressure and RT (25-30 DEG C).After the completion of hydrogenation, under a nitrogen atmosphere, Filtration of catalyst, filtrate subtracts
Pressure concentration removes solvent, and obtaining brown color compound is V crude compound 10.9g of formula.HPLC purity: RR and SS isomers:
97.74%, RS and SR isomers: 0.79%
The purifying of V compound of formula:
Under the conditions of 65-70 DEG C, above-mentioned crude product (10.9g) is dissolved in isopropyl ether (54.5mL), active carbon is added and stirs
It mixes and filters, filtrate is then slowly cooled to room temperature (25-30 DEG C) and filters, obtaining brown color crystallization is V compound of formula
8.7g.MR:97.5-99.5 DEG C, HPLC purity: RR and SS isomers: 97.85%, RS and SR isomers: 0.64%
3) N- [5- (2- { benzyl [2- (4- methoxyphenyl) -1- Methylethyl] amino } -1- hydroxyethyl) -2- benzyloxy
Base phenyl] (VI) preparation
Acetic anhydride (31.52g) is added into 1L four-hole boiling flask and is cooled to 0 DEG C with cooling bath.Under intense agitation,
Formic acid (15.96mL) is added dropwise with about 1mL/ minutes speed, the temperature of reaction mixture is made to be maintained at 5 DEG C or less.After 30 minutes,
Reaction solution is heated to 50-55 DEG C.After 2 hours, reaction solution is cooled to 5-10 DEG C.Under the conditions of 5-10 DEG C, into the solution
THF (260mL) solution of the crystallization aminoderivative (42g) of the formula V dissolved in advance is added.After adding, removing cooling bath simultaneously will
Reaction is stirred at room temperature overnight.It is concentrated under reduced pressure and removes solvent, oily residue is dissolved in ethyl acetate, and successively with 5%
Sodium bicarbonate aqueous solution and sodium carbonate liquor washing.Organic layer is stirred with active carbon, and clear solution is then obtained by filtration.Decompression
Concentration removes solvent, and is crystallized with isopropyl ether, obtains the crystalline compounds 42.0g of formula VI.Product is used under the conditions of 25-30 DEG C
Isopropanol (420mL) recrystallization, obtains VI white crystalline compound 40.2g of formula.MR:112.7-114.2 DEG C, HPLC purity: RR
With SS isomers: 98.07%, RS and SR isomers: 0.56%, acetylation impurity 1.5%.
4) N- (2- hydroxyl -5- { 1- hydroxyl -2- [2- (4- methoxyphenyl) -1- methylethylamine] ethyl } phenyl first
The preparation of amide VII
The ethyl acetate of VI crystalline compounds of formula (40g) dissolved in advance is added into 1L stainless steel hydrogenation reaction cauldron
(250mL) solution.Methanol (250mL) suspension of 10% palladium charcoal (16g) is added into the solution.And under the conditions of 40-60psi
Hydrogenation.After the completion of hydrogenation, under a nitrogen atmosphere, Filtration of catalyst, and under the conditions of 30-40 DEG C, filtrate decompression is concentrated
Remove solvent.Ethyl acetate (350mL) then isopropanol (250mL) is added at 35-40 DEG C in gained compound, and in 30-35
Crystallization under the conditions of DEG C, obtaining white solid is VII compound 15g of formula.HPLC purity: RR and SS:99.13%, RS and SR isomery
Body: 0.29%, impurity " A ": 0.23%, impurity " C ": 0.19%, impurity " F ": 0.07%, impurity " E ": 0.04%, remaining is miscellaneous
Matter B, D, G, H are not detected.
5) preparation of formoterol fumarate Ι (B)
Above-mentioned white solid formula VII (15g) and toluene (150mL) are added into 500mL four-hole boiling flask.(25- at room temperature
30 DEG C) into the suspension of the stirring, isopropanol (30mL) solution of the fumaric acid (2.40g) dissolved in advance is added.In room temperature
Under the conditions of after lower stirring 5 hours, filtering by obtained material 95% isopropanol water solution (300ml) stirring, and is heated to 65-
75 DEG C, 1-2h is kept, reactive material is then cooled to 40-45 DEG C, keeps 1-2h, filtering.Wet product is put into flask and is added
Acetonitrile (460mL) stirring, and it is heated to 75-80 DEG C.1-2h is kept, then reactant is cooled to 40-45 DEG C, keeps 1-2h, mistake
It filters, is dried in vacuo at a temperature of 60 DEG C, obtains Ι (B) compound 10.1g.HPLC purity: RR and SS:99.08%, RS and SR isomery
Body: 0.26%, impurity " A ": 0.29%, impurity " C ": 0.17%, impurity " F ": 0.15%, impurity " E ": 0.02%, remaining is miscellaneous
Matter B, D, G, H are not detected.
6) formoterol fumarate dihydrate Ι (C) is prepared
Above-mentioned formula Ι (B) compound (10.1g) and water (64mL) are ground 30 minutes together under the conditions of RT (25-30 DEG C),
Then it filters, wet cake is washed with water, then be dried in vacuo at 60 DEG C, obtaining white solid is formula Ι (C) compound 10.0g.
HPLC purity: 99.15%, impurity " A ": 0.23%, impurity " C ": 0.16%, impurity " F ": 0.14%, impurity " E ": 0.02%,
Remaining impurity B, D, G, H are not detected.Enantiomeric purity (HPLC): RR and SS:99.10%, RS and SR isomers:
0.28%.
It is from above-mentioned preparation process it is found that cumbersome using repeatedly crystallization, hot conditions in whole preparation process；Good fortune is not
The preparation purity of special sieve VII is lower, has multiple impurity to detect, and the repeatedly purifying of subsequent needs increases production cost；The preparation of Ι (B)
It carries out under the high temperature conditions, causes product stability poor, impurity increases obvious；Ι (C) is dried in vacuo in the presence of loss knot at 60 DEG C
The risk of brilliant water.
The above embodiments are only the preferred technical solution of the present invention, and are not construed as limitation of the present invention, the application
In embodiment and embodiment in feature in the absence of conflict, can mutual any combination.Protection scope of the present invention
Should be with the technical solution of claim record, the equivalents of technical characteristic in the technical solution recorded including claim
For protection scope, i.e., equivalent replacement is improved within this range, also within protection scope of the present invention.
Claims (10)
1. a kind of purification process of Formoterol intermediate (V compound represented of formula), this method comprises the following steps:
I) salt-forming reaction occurs in organic solvent A for V compound represented crude product of formula and fumaric acid, and V shownization of formula is made
Close the fumarate of object；
II) making step I) neutralization reaction occurs in organic solvent B for the fumarate of compound shown in obtained formula V and alkali, it makes
V compound represented of formula that must be purified；
III) V compound represented of formula of the obtained purifying of step II) is crystallized in organic solvent C to get in Formoterol
Mesosome.
2. the method according to claim 1, wherein in step I), the organic solvent A is ester and alcohol, excellent
It is selected as ethyl acetate and alcohol, more preferably ethyl acetate and low-grade alkane alcohol (such as methanol, ethyl alcohol)；
Preferably, in step I), the fumarate of compound shown in the formula V the preparation method is as follows:
V compound represented crude product of formula and ethyl acetate are heated to 60-75 DEG C, add fumaric acid and alcohol, stirring and dissolving,
Until completely dissolved, be cooled to 20-35 DEG C, stir 1-2h, continue to be down to -10-20 DEG C of Nei Wen, stirring and crystallizing 1-2h to get；
Preferably, in step I), the fumarate of compound shown in the formula V the preparation method is as follows:
V compound represented crude product of formula and ethyl acetate are heated to 70-75 DEG C, add fumaric acid and alcohol, stirring and dissolving,
Until completely dissolved, be cooled to 20-30 DEG C, stir 1-2h, continue to be down to 0-10 DEG C of interior temperature, stirring and crystallizing 1-2h to get；
Preferably, in step I), the alcohol in the organic solvent A is selected from one of methanol, ethyl alcohol and isopropanol or a variety of,
Preferably methanol or ethyl alcohol, more preferably methanol.
3. method according to claim 1 or 2, which is characterized in that in step II), shown in the formula V of the purifying
Compound the preparation method is as follows:
The fumarate of compound shown in formula V that step I) is obtained and alkali are heated to 20-40 DEG C of interior temperature in organic solvent B,
Be stirred to react 4-6h to get；
Preferably, in step II), V compound represented of formula of the purifying the preparation method is as follows:
The fumarate of compound shown in formula V that step I) is obtained and alkali are heated to 30-40 DEG C of interior temperature in organic solvent B,
Be stirred to react 4-6h to get；
Preferably, in step II), the organic solvent B is methylene chloride, ethyl acetate or acetonitrile, preferably methylene chloride
Or ethyl acetate, more preferably methylene chloride；
Preferably, in step II), sodium carbonate liquor or 10w/v%-20w/v% that the alkali is 10w/v%-20w/v%
Solution of potassium carbonate, the preferably sodium carbonate liquor of 10w/v%-20w/v%, the more preferably sodium carbonate liquor of 10w/v%.
4. according to the method in any one of claims 1 to 3, which is characterized in that in step III), the Formoterol
Intermediate the preparation method is as follows:
V compound represented of formula of the obtained purifying of step II) is heated to 50-70 DEG C in organic solvent C, stirring and dissolving,
Until completely dissolved, it is slowly dropped to 15-35 DEG C of interior temperature, stirring and crystallizing 2-3h is to get Formoterol intermediate；
Preferably, in step III), the Formoterol intermediate the preparation method is as follows:
Step II) obtained V compound represented of formula of purifying is heated to 60-70 DEG C in organic solvent C, stirring and dissolving, to
After being completely dissolved, it is slowly dropped to 20-30 DEG C of interior temperature, stirring and crystallizing 2-3h is to get Formoterol intermediate；
Preferably, in step III), the organic solvent C is ethyl alcohol, ethyl acetate or the isopropyl ether of 50v/v%, preferably
The ethyl alcohol or isopropyl ether of 50v/v%, more preferably isopropyl ether；
Preferably, in step III), the step II) obtained V compound represented of formula of purifying and the solvent C it
Between ratio be 1g:8.0mL-1g:15.0mL, preferably 1g:10.0mL-1g:12.0mL.
5. a kind of purification process of Formoterol (V II compound represented of formula), this method comprises the following steps:
1) Formoterol crude product is extruded with nitrogen, filters, is washed with organic solvent D；
2) by the resulting filtrate decompression concentration and evaporation of step 1)；
3) organic solvent E and organic solvent F is added in the product obtained to step 2) evaporation, stirring is beaten to get Fu Mote
Sieve.
6. according to the method described in claim 5, it is characterized in that, the organic solvent D is methanol and acetic acid in step 1)
Ethyl ester mixed solution, methanol, ethyl alcohol or tetrahydrofuran, preferably methanol and ethyl acetate mixture.
7. method according to claim 5 or 6, which is characterized in that in step 2), reduced pressure evaporation be
Under 30-40 DEG C of water bath condition, carried out under preferably 30 DEG C -35 DEG C of water bath condition.
8. method according to any one of claims 5 to 7, which is characterized in that in step 3), the organic solvent E
For methylene chloride, 1,2- dichloroethanes or chloroform, preferably methylene chloride；
Preferably, the organic solvent F is methanol, ethyl alcohol 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。
9. the method according to any one of claim 5 to 8, which is characterized in that in step 1), the Formoterol is thick
The preparation method of product includes the following steps:
I) in the presence of condensing agent and organic solvent G formylation reaction is occurred into for V compound represented of formula, anhydrous formic acid, tied
VI compound represented of formula is made in crystalline substance；
Ii) VI compound represented of formula in the presence of catalyst and organic solvent H to that reduction reaction occur thick to get Formoterol
Product (Formoterol reaction solution)；
Preferably, in step i), the condensing agent is 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride
(EDCI), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) or dicyclohexyl carbon two
Imines (DCC), preferably EDCI；
Preferably, in step i), the organic solvent G is selected from methylene chloride, 1,2- dichloroethanes, chloroform and ethyl acetate
One or more, preferably methylene chloride or 1,2- dichloroethanes, more preferably methylene chloride；
Preferably, in step ii), the catalyst is the palladium charcoal or Raney's nickel of 5w/w%-10w/w%, preferably 5w/w%-
The palladium charcoal of 10w/w%, the palladium charcoal of more preferably 10w/w%；
Preferably, in step ii), the organic solvent H is methanol and ethyl acetate mixture, methanol, ethyl alcohol or tetrahydro
Furans, preferably methanol and ethyl acetate mixture；
Preferably, in step i), V compound represented of formula is by method system described in any one of Claims 1-4
It is standby.
10. a kind of preparation method for preparing formoterol fumarate (Formulas I compound represented), this method includes following step
It is rapid:
VII compound represented of formula and fumaric acid are occurred in the presence of methanol, dimethyl sulfoxide (DMSO), organic solvent I and water
Salt-forming reaction, then crystallize to get；
Preferably, the organic solvent I is acetone, methylene chloride, butanone, ethyl acetate or acetonitrile, preferably butanone, acetic acid second
Ester or acetonitrile, most preferably butanone；
Preferably, prepared by VII compound represented of formula method described in any one of claim 5 to 9.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110376313A (en) * | 2019-08-20 | 2019-10-25 | 广州健康元呼吸药物工程技术有限公司 | A method of impurity in detection formoterol fumarate or its related preparations |
| CN112574055A (en) * | 2019-09-30 | 2021-03-30 | 天津天药药业股份有限公司 | Preparation method and application of formoterol and medicinal salt thereof |
| CN113999185A (en) * | 2021-11-18 | 2022-02-01 | 浙江海洲制药有限公司 | Preparation method of high-purity Magnetic Resonance Imaging (MRI) drug intermediate |
| CN114213285A (en) * | 2021-12-29 | 2022-03-22 | 斯坦德标准技术研究(湖北)有限公司 | Formoterol related substance, preparation method and application thereof |
| CN115368250A (en) * | 2022-09-02 | 2022-11-22 | 博诺康源(北京)药业科技有限公司 | Method for splitting formoterol chiral intermediate |
| CN116908345A (en) * | 2023-07-10 | 2023-10-20 | 南京力成药业有限公司 | Method for detecting content of formoterol fumarate inhalation solution |
| CN116930381A (en) * | 2023-07-04 | 2023-10-24 | 南京力成药业有限公司 | Method for detecting diastereoisomeric impurities in formoterol fumarate inhalation solution |
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| WO2008035380A2 (en) * | 2006-09-19 | 2008-03-27 | Natco Pharma Limited | An improved process for the preparation of high purity formoterol and its pharmaceutically acceptable salts |
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| US3994974A (en) * | 1972-02-05 | 1976-11-30 | Yamanouchi Pharmaceutical Co., Ltd. | α-Aminomethylbenzyl alcohol derivatives |
| JPS56115751A (en) * | 1980-06-11 | 1981-09-11 | Yamanouchi Pharmaceut Co Ltd | Preparation of novel 3-acylamino-4-hydroxy-alpha- aralkylaminomethyl benzyl alcohol |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110376313A (en) * | 2019-08-20 | 2019-10-25 | 广州健康元呼吸药物工程技术有限公司 | A method of impurity in detection formoterol fumarate or its related preparations |
| CN110376313B (en) * | 2019-08-20 | 2022-06-07 | 广州健康元呼吸药物工程技术有限公司 | Method for detecting impurities in formoterol fumarate or related preparation thereof |
| CN112574055A (en) * | 2019-09-30 | 2021-03-30 | 天津天药药业股份有限公司 | Preparation method and application of formoterol and medicinal salt thereof |
| CN113999185A (en) * | 2021-11-18 | 2022-02-01 | 浙江海洲制药有限公司 | Preparation method of high-purity Magnetic Resonance Imaging (MRI) drug intermediate |
| CN113999185B (en) * | 2021-11-18 | 2023-09-29 | 浙江海洲制药有限公司 | Preparation method of high-purity Magnetic Resonance Imaging (MRI) drug intermediate |
| CN114213285A (en) * | 2021-12-29 | 2022-03-22 | 斯坦德标准技术研究(湖北)有限公司 | Formoterol related substance, preparation method and application thereof |
| CN114213285B (en) * | 2021-12-29 | 2022-07-29 | 斯坦德标准技术研究(湖北)有限公司 | Formoterol related substance, preparation method and application thereof |
| CN115368250A (en) * | 2022-09-02 | 2022-11-22 | 博诺康源(北京)药业科技有限公司 | Method for splitting formoterol chiral intermediate |
| CN116930381A (en) * | 2023-07-04 | 2023-10-24 | 南京力成药业有限公司 | Method for detecting diastereoisomeric impurities in formoterol fumarate inhalation solution |
| CN116908345A (en) * | 2023-07-10 | 2023-10-20 | 南京力成药业有限公司 | Method for detecting content of formoterol fumarate inhalation solution |
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