CN101717392A - Method for preparing rotigotine and derivative thereof - Google Patents
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- CN101717392A CN101717392A CN200910186194A CN200910186194A CN101717392A CN 101717392 A CN101717392 A CN 101717392A CN 200910186194 A CN200910186194 A CN 200910186194A CN 200910186194 A CN200910186194 A CN 200910186194A CN 101717392 A CN101717392 A CN 101717392A
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Abstract
The invention discloses a method for preparing a compound of a formula (I) or pharmaceutically acceptable salts thereof. The method is characterized by comprising the following steps of: (1) using a compound of a formula (II) as a raw material and carrying out a reduction and amination reaction with an appropriate reducing agent to obtain a compound of a formula (III); (2) using 2-quinary heterocyclic substituted ethanol as a raw material and reacting to obtain a compound of a formula (IV) under the conditions of appropriate reagent, temperature and solvent; (3) after carrying out chiral separation on the compound of the formula (III), carrying out a condensation reaction with the compound of the formula (I) under an alkaline condition to obtain a compound of a formula (V); and (4) carrying out demethylation protection on the compound of the formula (V) under the condition of appropriate temperature and solvent to obtain the compound of the formula (I), wherein R1 in each formula is selected from C1-8 alkyl groups or aromatic bases which can be arbitrarily substituted, X is selected from halogen atoms or p-toluenesulfonic acid groups and methanesulfonic acid groups for protecting alcoholic extract hydroxyl groups, and Y is selected from O, S and N. A target product obtained by the method has high optical purity, convenient operation, lower cost, higher yield and less pollution and is suitable for industrialized production.
Description
Technical field
The invention belongs to the pharmaceutical technology field, be specifically related to a kind of method for preparing rotigotine and derivative thereof.
Background technology
(Parkinson disease PD) claims Parkinsonism again to Parkinson's disease, is middle-aged and old modal central nervous system degenerative diseases.Trembling is that finger and four limbs tremble, jolting, and paralysis is meant that part or all limbs of limbs can not autokinetic movement.Its classical symptom comprises dyskinesia, trembles and muscular rigidity.Generally began morbidity at 50～65 years old, sickness rate increases gradually with age growth, and sickness rate was about 1 ‰ in 60 years old, and sickness rate reached 3 ‰～5 ‰ in 70 years old, and China probably has more than 170 ten thousand people to suffer from this disease at present.Data shows at present, a little higher than women of the male sex among the Parkinson's disease morbidity crowd, and the treatment to this disease up to now is symptomatic treatment, does not still have the radical cure method neurocyte of sex change is recovered.
The parkinsonian cause of disease also is not very clear now.Generally acknowledge that at present its cause of disease is the degeneration of neurocyte, the major lesions position is at black substance and striatum.The progressively forfeiture of minimizing, function gradually of nigral cell quantity in black substance and the striatum causes a kind of material of Dopamine HCL that cries to reduce, thereby causes above-mentioned symptom.Think that according to experimentation on animals and EPDML result Parkinson's disease and heredity also have certain relation.According to pathogenic factor, can be divided into two classes to the Parkinsonism symptom, a class is called the essential tremor paralysis, and promptly can not find clear and definite reason or pathogenic factor may have relation with heredity, and we are called Parkinson's disease or Parkinson's disease with it.Another kind ofly be called Secondary cases Parkinsonism, promptly because of certain encephalitis, poisoning (as carbon monoxide, manganese, prussiate, poisoning by reserpine, phenothiazines and drug intoxication such as butyryl phthalein benzene class medicine and tricyclic antidepressants antidepressant etc.), cerebro-vascular diseases, craniocerebral injury, cerebral tumor, Deng causing, be called Parkinson or parkinson's syndrome, Parkinsonism again.
Along with the adjustment of aged's ratio and medication structure, bigger growth appears in Parkinsonian number of patients and antiparkinsonism drug market in recent years.Global antiparkinsonism drug sales volume amounted to 1,500,000,000 dollars in 2000, and 2004 is 2,500,000,000 dollars, and total market comsupton every year is with 25% speed increment.The Parkinson's disease morbidity of China and market development and American-European countries are similar, the whole nation 1412 tame sample hospital Parkinson's disease medication service condition analysis revealeds in 2005, the actual Parkinson's disease medication sales volume in the whole nation is about 4.2 hundred million yuans, than having increased by 11.45% last year, make a general survey of Parkinsonian medium-term and long-term market, this type of medicine will have very large development potentiality.
Parkinson's disease mainly adopts pharmacological agent and operative treatment at present.Early stage in disease, medicine can improve symptom well, the most frequently used also is that the most effective medicine is a Dopar, however this medicine must take for a long time, in case stop treatment, the state of an illness can recur.Initial several years medication effect the bests, though most patient's prolonged application is still effective, after taking for a long time, patient can feel medicine shortening working lipe, and some patient can produce " agent end " phenomenon and " open and close " fluctuation.Pharmacological agent has certain limitation, and can become through the state of an illness after the treatment of 3-5 usually is difficult to control, and Side effects of pharmaceutical drugs and its curative effect can merits offset faults, and patient feels that activity of daily living is very limited.The shortcoming of operative treatment maximum is easy recurrence, is irreversible treatment, uses comparatively limitation.
Rotigotine is by German Schwarz company (Schwarz Biosciences) development, can be used for early stage Secondary cases Parkinson's disease and Parkinsonian treatment in late period, and its commodity are called Neupro.In May, 2007 its listing of drugs approved by FDA, it is the first percutaneous plaster that is used for the treatment of Parkinsonism.Research finds that also the early stage special property the sent out Parkinson's disease of dopamine-receptor stimulant rotigotine transdermal patch treatment are effective, patient's well-tolerated; And the early stage special property Parkinson's disease of sending out of rotigotine transdermal patch treatment have following advantage: can be continuously, continue the release medicine, eliminate first pass effect, the blood level of stable state is provided, has avoided the pulsed of Dopamine Receptors is stimulated, stop and delay neuronic sex change; Reduce unexpected " interruption " state of oral drug therapy; Reduce motor fluctuation that medicines such as taking levodopa easily causes, on-off phenomenon etc.; Increase patient's compliance and caregiver's accessibility.
Rotigotine, (-)-(S)-2-[N-propyl group-N-[2-(2-thiophene) ethyl] amino]-5-hydroxyl-1,2,3, the 4-naphthane, structure is as follows,
Its CAS accession number is 92206-54-7, and what use always in the pharmacy is its hydrochloride, and structure is as follows:
The synthesis route of the rotigotine of existing report or its hydrochloride is as follows in the prior art:
In this synthetic method, use the bigger benzylamine of toxicity, iodopropane and 2-butanone in a large number, and need to use shortening, make and synthesize the cost costliness; Use tartaric acid derivatives to split, the optical purity of product is undesirable; The side reaction that generates in the reaction process simultaneously is more, and product is difficult for purifying, and reactive applications obtains restriction, and this synthetic method is not suitable for suitability for industrialized production.Yet, seek a kind of convenience and the synthetic method that is easy to control cost is very significant in view of rotigotine and derivative thereof have good pharmacy value and market outlook.The present invention comes therefrom.
Summary of the invention
The object of the invention is to provide a kind of new method for preparing rotigotine and derivative thereof, has solved in the prior art the low problem such as purifying that is difficult to of rotigotine preparation cost costliness, suitability for industrialized production difficulty, yield.
In order to solve these problems of the prior art, technical scheme provided by the invention is:
The compound of a kind of preparation formula (I)
Or the method for its pharmacy acceptable salt, it is characterized in that said method comprising the steps of:
(1) with the compound of formula (II)
Obtain the compound of formula (III) for raw material and suitable reductive agent reduction amination;
(2) replacing ethanol with the 2-five-membered ring is raw material, and under suitable reagent, temperature and solvent condition, reaction obtains the compound of formula (IV);
(3) make the compound chirality of formula (III) split the compound that condensation reaction under the compound alkaline condition of back and formula (IV) obtains formula V;
(4) compound that makes formula V demethylation protection under suitable temperature, solvent condition obtains the compound of formula (I);
R in wherein various
1Be selected from the aromatic base that the C1-8 alkyl maybe can be optionally substituted; X is selected from the protection halogen atom of alcoholic extract hydroxyl group or tosic acid base, methylsulphonic acid base; Y is selected from O, S, N.
Preferably, the compound chirality method for splitting of described method steps (3) Chinese style (III) comprises the organic phospho acid by suitable Chiral Amine preparation formula (VI);
And the compound of the organic phospho acid chiral separation formula (III) of through type (VI)
Obtain having the compound of the formula (III ') of chirality;
R in various
1Be selected from the aromatic base that the C1-8 alkyl maybe can be optionally substituted; R
2, R
3All be selected from the alkyl of C1-3, the aromatic base that can be optionally substituted; Z is selected from the aromatic base that the alkyl of halogen atom, C1-4 maybe can be optionally substituted, and Z is on the ortho position or contraposition of phenyl ring.
Preferably, Chiral Amine is selected from least a in (D/L)-phenylalanine, (D/L)-proline(Pro), (D/L)-phenylglycine, (D/L)-D-pHPG, (D/L)-phenylethylamine, (the D/L)-naphthalene ethylamine in the described method.
Preferably, reductive agent is selected from least a in sodium borohydride, POTASSIUM BOROHYDRIDE, zinc powder, iron powder, hydrazine hydrate, the hydrogen in the described method steps (1); Its reduction amination temperature is controlled at 0-100 ℃.
Preferably, alkaline environment described in the described method steps (3) is for existing following a kind of material at least: sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, triethylamine, pyridine, DMAP; The described solvent that is reflected at is selected under the situation that a kind of solvent of being selected from toluene, dimethylbenzene, tetrahydrofuran (THF), DMF, DMSO at least exists and carries out; Temperature of reaction is controlled at 0-50 ℃.
Preferably, the temperature of demethylation protective reaction is controlled at 100-180 ℃ in the described method steps (4); The solvent that reaction is adopted is selected from least a of toluene, dimethylbenzene, DMF, DMSO; Use demethylation reagent to be selected from least a in hydroiodic acid HI, Hydrogen bromide, boron trichloride, boron tribromide, aluminum chloride, boron trifluoride ethyl ether complex, sulfur alcohol sodium, the lithium chloride.
Preferably, described compound pharmacy acceptable salt is selected from hydrochloride, vitriol, phosphoric acid salt, metilsulfate, acetate, trifluoroacetate; Described compound pharmacy acceptable salt can be by the compound of (I)
Obtain formula (VII) compound with corresponding acid-respons
R in wherein various
1Be selected from the aromatic base that the C1-8 alkyl maybe can be optionally substituted; Y is selected from O, S, N.
Preferably, in the described method range of reaction temperature at-10-20 ℃; HR
4Be selected from hydrochloric acid, sulfuric acid, phosphoric acid, methylsulphonic acid, acetate, trifluoroacetic acid; Reaction solvent is selected from ethyl acetate, methyl alcohol, and ethanol, methylene dichloride, toluene, tetrahydrofuran (THF) at least a, the reacting system PH value scope is between 1-4.
The synthetic route of rotigotine of the present invention and derivative thereof is as follows:
In the synthesis path of the present invention, at first the 2-Tetralone an intermediate of Sertraline that replaces with methoxyl group is a starting raw material, carry out reduction amination and obtain methoxyl group replacement 2-(N-substituted-amino)-tetraline, with above-mentioned synthetic compound, under novel phosphonic acids effect, the methoxyl group that fractionation obtains chirality replaces 2-(N-substituted-amino)-tetraline, with the compound that obtains in above-mentioned (III ') under certain temperature and solvent condition, obtain compound (V) with compound (IV) reaction, range of reaction temperature is at 0-50 ℃.Under certain temperature, solvent condition, the demethylation protection obtains compound (I) with the compound (V) that obtains in above-mentioned.The compound (VI) that obtains in above-mentioned under certain temperature, solvent condition, is introduced corresponding acid and obtained target product (VII).Wherein, the key intermediate of synthetic rotigotine and derivative thereof is the compound of formula with chirality (III ');
With respect to scheme of the prior art, advantage of the present invention is:
The optical purity height of the target product that production technique of the present invention obtains, easy and simple to handle, cost is lower, and yield is higher, pollutes lessly, is suitable for suitability for industrialized production.Rotigotine that the present invention prepares and derivative thereof are the important treatment Parkinson's disease medicine of a class, have good social benefit and economic benefit.
Embodiment
Below in conjunction with specific embodiment such scheme is described further.Should be understood that these embodiment are used to the present invention is described and are not limited to limit the scope of the invention.The implementation condition that adopts among the embodiment can be done further adjustment according to the condition of concrete producer, and not marked implementation condition is generally the condition in the normal experiment.
The preparation of embodiment 1 rotigotine
The preparation of 2-(N-n-propyl amino)-5-methoxyl group tetraline
5-methoxyl group-2-Tetralone an intermediate of Sertraline (3.52 grams, 20 mmoles) and propylamine (3.3 milliliters, 40 mmoles) are dissolved in 50 milliliters of dehydrated alcohols, add the p-methyl benzenesulfonic acid of catalytic amount then, and reflux stirred 2～5 hours; Reaction mixture is cooled to 0 ℃, stirs down, slowly add sodium borohydride (1.14 grams, 30 mmoles), slowly be warming up to 30 ℃ then, under this temperature condition, continue to stir 24 hours.Remove organic solvent, add 100 milliliter 10% sodium hydroxide solution, stirred 1 hour, use 100 milliliters of dichloromethane extractions then, continuous extraction three times.The organic solvent anhydrous sodium sulfate drying filters, and extraction solvent obtains oily matter 3.2 grams (62%).
The preparation of chirality organic phospho acid
1 normal potassium hydroxide-ethanol solution slowly is added drop-wise in 1 normal o-chlorobenzaldehyde and the 2.5 normal mixture of isobutyraldehyde, spends the night 60～65 ℃ of reactions, the glycol that obtains through aftertreatment is directly used in the reaction of back.In the dichloromethane solution of 1 mole above-mentioned glycol, slowly drip 1.5 moles phosphorus oxychloride, reflux is 5 hours then, obtains the racemize organic phospho acid through conventional aftertreatment.
The racemize organic phospho acid of equivalent and Chiral Amine heating for dissolving in 1: 1 ethanol-water solution, are slowly cooled down to stir and spend the night, suction filtration, solid washes with water; The hydrochloric acid of resulting solid and 1: 5 was stirred 6 hours, suction filtration, the solid water repeatedly washs, and drying obtains chipal compounds.After testing,
The preparation of optically active 2-(N-n-propyl amino)-5-methoxyl group tetraline
In 2-(N-n-propyl amino)-5-methoxyl group tetraline (5.47 grams, 25 mmoles) and (+)-chirality phosphonic acids (6.92 grams, 25 mmoles), add 50 milliliters of ethanol and 20 ml waters, heating is all dissolved solid, stirs down, slowly cool to room temperature; Continue to stir 6 hours, suction filtration, filter cake repeatedly wash with ethanol, ether respectively.Add 50 ml waters in filter cake, regulating pH with 20% sodium hydroxide is 10, and stirring at room 1 hour is used 50 milliliters of dichloromethane extractions then, continuous extraction three times.The organic solvent anhydrous sodium sulfate drying filters, and removing desolvates obtains optically active 2-(N-n-propyl amino)-5-methoxyl group tetraline, 1.04 grams (38%).
The preparation of 2-thiophene ethyl p-toluenesulfonic esters
2-thiophene ethanol (2.5 grams, 19.1 mmoles) and Tosyl chloride (4.02 grams, 21.1 mmoles) are dissolved in 50 milliliters of methylene dichloride, and are cooled to 0 ℃; Stir down, slowly triethylamine (5.3 milliliters, 38.3 mmoles) and 4-N, the dichloromethane solution of N-dimethyl aminopyridine (48 milligrams, 0.4 mmole) is added drop-wise in the above-mentioned reaction mixture in 1 hour.React after 24 hours, reaction mixture is poured in the frozen water, add 30 milliliters of 2N hydrochloric acid then and stirred 1 hour, use 50 milliliters of dichloromethane extractions then, continuous extraction three times; Merge organic layer, salt solution washing secondary, the organic solvent anhydrous sodium sulfate drying filters, and removing desolvates obtains faint yellow oily thing, 5.12 grams.
The preparation of chirality 2-(N-n-propyl amino-N-(2-thiophene ethyl))-5-methoxyl group tetraline
Chirality 2-(N-n-propyl amino)-5-methoxyl group tetraline (0.88 gram, 4 mmoles) and 2-thiophene ethyl p-toluenesulfonic esters (1.24 grams, 4.4 mmoles) are dissolved in 30 milliliters of dimethylbenzene, add anhydrous sodium carbonate (0.26 gram, 2.4 mmoles) then; This reaction mixture is under nitrogen protection, and reflux 36 hours reduces pressure and removes organic solvent, and the direct column chromatography of residuum obtains, 1.08 grams, (82%).
The preparation of chirality-2-(N-n-propyl amino-N-(2-thiophene ethyl))-5-hydroxy tetrahydro naphthalene
30 milliliters of the Hydrogen bromides of adding 48% in chirality-2-(N-n-propyl amino-N-(2-thiophene ethyl))-5-methoxyl group tetraline (1.08 gram) add then and refluxed 4 hours; Ice-salt bath is cooled to 0 degree, and the ammoniacal liquor alkalization with 37% is used 100 milliliters of ethyl acetate extractions, continuous extraction three times then; Merge organic layer, salt solution washing secondary, the organic solvent anhydrous sodium sulfate drying filters, and removing desolvates obtains oily matter, 0.94 gram, (91%, 99%ee).
1HNMR(400MHz，CDCl
3)：7.12(d，J＝5.88Hz，1H)，6.99(t，J＝7.74Hz，1H)，6.94-6.92(m，1H)，6.83(d，J＝1.76Hz，1H)，6.69(d，J＝7.56Hz，1H)，6.61(d，J＝7.92Hz，1H)，3.02-2.95(m，3H)，2.92-2.84(m，4H)，2.60-2.56(m，3H)，2.24-2.11(m，1H)，1.68-1.61(m，1H)，1.55-1.48(m，2H)，0.91(t，J＝7.32Hz，3H).
13CNMR(100MHz，CDCl
3)：154.29，142.19，137.27，126.82，126.43，124.94，123.57，123.32，121.01，112.26，57.47，52.65，52.49，31.77，28.85，25.42，23.69，21.21，11.96.
The preparation of embodiment 2 rotigotine hydrochlorides
The preparation of 2-(N-n-propyl amino)-5-methoxyl group tetraline
5-methoxyl group-2-Tetralone an intermediate of Sertraline (3.52 grams, 20 mmoles) and propylamine (3.3 milliliters, 40 mmoles) are dissolved in 50 milliliters of dehydrated alcohols, add the camphorsulfonic acid of catalytic amount then, and reflux stirred 2～5 hours; The reaction mixture cool to room temperature, add the palladium-carbon catalyst of catalytic amount, add the POTASSIUM BOROHYDRIDE room temperature and continue to stir 24 hours.Suction filtration is removed palladium carbon, with 50 milliliters of washed with dichloromethane, merges organic liquor, concentrates to obtain oily matter 3.3 grams.
The preparation of chirality organic phospho acid
1 normal o-chlorobenzaldehyde and 2.5 normal isobutyric aldehydes are mixed, and controlled temperature slowly drips 1 normal potassium hydroxide-ethanol solution wherein, spends the night 60～65 ℃ of reactions then, and extraction concentrates and obtains the reaction that glycol is directly used in the back.In the dichloromethane solution of 1 mole above-mentioned glycol, slowly drip 1.5 moles phosphorus oxychloride, reflux is 5 hours then, obtains the racemize organic phospho acid through conventional aftertreatment.
The racemize organic phospho acid of equivalent and D-proline(Pro) heating for dissolving in 1: 1.2 ethanol-water solution, are cooled down to stir and spend the night, suction filtration, solid washes with water; Resulting solid and 10% sulfuric acid were stirred 6 hours, suction filtration, the solid water repeatedly washs, and drying obtains the chirality phosphonic acids.
The preparation of optically active 2-(N-n-propyl amino)-5-methoxyl group tetraline
In 2-(N-n-propyl amino)-5-methoxyl group tetraline (5.47 grams, 25 mmoles) and (+)-chirality phosphonic acids (6.92 grams, 25 mmoles), add 60 milliliters of ethanol and 25 ml waters, heating is all dissolved solid, stirs down, slowly is cooled to 0 ℃; Continue to stir 6 hours, suction filtration, filter cake repeatedly wash with ethanol, ether respectively.Add 50 ml waters in filter cake, regulating pH with yellow soda ash is 10, and stirring at room 1 hour is used 50 milliliters of dichloromethane extractions then, continuous extraction three times.The organic solvent anhydrous sodium sulfate drying filters, and removing desolvates obtains optically active 2-(N-n-propyl amino)-5-methoxyl group tetraline, 1.08 grams.
The preparation of 2-thiophene ethyl methane sulfonate ester
2-thiophene ethanol (2.5 grams, 19.1 mmoles) is dissolved in 50 milliliters of methylene dichloride, adds triethylamine (5.3 milliliters, 38.3 mmoles) and 4-N then, N-dimethyl aminopyridine (48 milligrams, 0.4 mmole), and be cooled to 0 ℃; Stir down, in 1 hour slowly methylsulfonyl chloride (2.74 grams, 21.1 mmoles) drop be added in the above-mentioned reaction mixture.React after 24 hours, reaction mixture is poured in the frozen water, add 30 milliliters of 2N hydrochloric acid then and stirred 1 hour, use 50 milliliters of dichloromethane extractions then, continuous extraction three times; Merge organic layer, salt solution washing secondary, the organic solvent anhydrous sodium sulfate drying filters, and removing desolvates obtains faint yellow oily thing.
The preparation of chirality 2-(N-n-propyl amino-N-(2-thiophene ethyl))-5-methoxyl group tetraline
Chirality 2-(N-n-propyl amino)-5-methoxyl group tetraline (0.88 gram, 4 mmoles) and 2-thiophene ethyl methane sulfonate ester (0.91 gram, 4.4 mmoles) are dissolved in 30 milliliters of toluene, add anhydrous sodium carbonate (0.26 gram, 2.4 mmoles) then; This reaction mixture is under nitrogen protection, and reflux 36 hours reduces pressure and removes organic solvent, and the direct column chromatography of residuum obtains, 1.20 grams.
The preparation of chirality-2-(N-n-propyl amino-N-(2-thiophene ethyl))-5-hydroxy tetrahydro naphthalene
Chirality-2-(N-n-propyl amino-N-(2-thiophene ethyl))-5-methoxyl group tetraline (1.08 gram) is dissolved in 30 milliliters of toluene, adds 5 gram boron trichloride etherates, add then and refluxed 4 hours; Ice-salt bath is cooled to 0 degree, with the saturated aqueous sodium carbonate alkalization, uses 100 milliliters of ethyl acetate extractions then, continuous extraction three times; Merge organic layer, salt solution washing secondary, the organic solvent anhydrous sodium sulfate drying filters, and removing desolvates obtains oily matter, 1.0 grams.
1HNMR(400MHz，CDCl
3)：7.12(d，J＝5.88Hz，1H)，6.99(t，J＝7.74Hz，1H)，6.94-6.92(m，1H)，6.83(d，J＝1.76Hz，1H)，6.69(d，J＝7.56Hz，1H)，6.61(d，J＝7.92Hz，1H)，3.02-2.95(m，3H)，2.92-2.84(m，4H)，2.60-2.56(m，3H)，2.24-2.11(m，1H)，1.68-1.61(m，1H)，1.55-1.48(m，2H)，0.91(t，J＝7.32Hz，3H).
13CNMR(100MHz，CDCl
3)：154.29，142.19，137.27，126.82，126.43，124.94，123.57，123.32，121.01，112.26，57.47，52.65，52.49，31.77，28.85，25.42，23.69，21.21，11.96.
The preparation of rotigotine hydrochloride
Chirality-2-(N-n-propyl amino-N-(2-thiophene ethyl))-5-hydroxy tetrahydro naphthalene (1 gram, 3.2 milligrams) is dissolved in 20 milliliters of dehydrated alcohols, and the frozen water cooling slowly adds 3 milliliters of concentrated hydrochloric acids; Ethanol is removed in decompression, adds 30 milliliters of ethanol decompressions again and removes, and repeats secondary, and residuum gets target product rotigotine 1.1 grams (98%) with the methylene dichloride recrystallization,
Above-mentioned example only is explanation technical conceive of the present invention and characteristics, and its purpose is to allow the people who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalent transformations that spirit is done according to the present invention or modification all should be encompassed within protection scope of the present invention.
Claims (8)
1. the compound of a preparation formula (I)
Or the method for its pharmacy acceptable salt, it is characterized in that said method comprising the steps of: (1) is with the compound of formula (II)
Obtain the compound of formula (III) for raw material and suitable reductive agent reduction amination;
(2) replacing ethanol with the 2-five-membered ring is raw material, and under suitable temperature and solvent condition, reaction obtains the compound of formula (IV);
(3) make the compound chirality of formula (III) split the compound that condensation reaction under the compound alkaline condition of back and formula (IV) obtains formula V;
(4) compound that makes formula V demethylation protection under suitable temperature, solvent condition obtains the compound of formula (I);
R in wherein various
1Be selected from the aromatic base that the C1-8 alkyl maybe can be optionally substituted; X is selected from the protection halogen atom of alcoholic extract hydroxyl group or tosic acid base, methylsulphonic acid base; Y is selected from O, S, N.
2. according to the method for claim 1, the compound chirality method for splitting that it is characterized in that described method steps (3) Chinese style (III) comprises the organic phospho acid by suitable Chiral Amine preparation formula (VI);
And the compound of the organic phospho acid chiral separation formula (III) of through type (VI)
Obtain having the compound of the formula (III ') of chirality;
R in various
1Be selected from the aromatic base that the C1-8 alkyl maybe can be optionally substituted; R
2, R
3All be selected from the alkyl of C1-3, the aromatic base that can be optionally substituted; Z is selected from the aromatic base that the alkyl of halogen atom, C1-4 maybe can be optionally substituted, and Z is on the ortho position or contraposition of phenyl ring.
3. method according to claim 2 is characterized in that Chiral Amine in the described method is selected from least a in (D/L)-phenylalanine, (D/L)-proline(Pro), (D/L)-phenylglycine, (D/L)-D-pHPG, (D/L)-phenylethylamine, (the D/L)-naphthalene ethylamine.
4. according to the method for claim 1, it is characterized in that reductive agent in the described method steps (1) is selected from least a in sodium borohydride, POTASSIUM BOROHYDRIDE, zinc powder, iron powder, hydrazine hydrate, the hydrogen; Its reduction amination temperature is controlled at 0-100 ℃.
5. according to the method for claim 1, it is characterized in that alkaline environment described in the described method steps (3) is for existing following a kind of material at least: sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, triethylamine, pyridine, DMAP; The described solvent that is reflected at is selected under the situation that a kind of solvent of being selected from toluene, dimethylbenzene, tetrahydrofuran (THF), DMF, DMSO at least exists and carries out; Temperature of reaction is controlled at 0-50 ℃.
6. according to the method for claim 1, it is characterized in that the temperature of demethylation protective reaction in the described method steps (4) is controlled at 100-180 ℃; The solvent that reaction is adopted is selected from least a of toluene, dimethylbenzene, DMF, DMSO; Use demethylation reagent to be selected from least a in hydroiodic acid HI, Hydrogen bromide, boron trichloride, boron tribromide, aluminum chloride, boron trifluoride ethyl ether complex, sulfur alcohol sodium, the lithium chloride.
7. according to the method for claim 1, it is characterized in that described compound pharmacy acceptable salt is selected from hydrochloride, vitriol, phosphoric acid salt, metilsulfate, acetate, trifluoroacetate; Described compound pharmacy acceptable salt can be by the compound of (I)
Obtain formula (VII) compound with corresponding acid-respons
R in wherein various
1Be selected from the aromatic base that the C1-8 alkyl maybe can be optionally substituted; Y is selected from O, S, N.
8. method according to claim 7 is characterized in that in the described method that range of reaction temperature is at-10-20 ℃; HR
4Be selected from hydrochloric acid, sulfuric acid, phosphoric acid, methylsulphonic acid, acetate, trifluoroacetic acid; Reaction solvent is selected from ethyl acetate, methyl alcohol, and ethanol, methylene dichloride, toluene, tetrahydrofuran (THF) at least a, the reacting system PH value scope is between 1-4.
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Cited By (53)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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