CN106397516B - Cangrelor intermediate and its preparation method and application - Google Patents
Cangrelor intermediate and its preparation method and application Download PDFInfo
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Abstract
The invention discloses cangrelor intermediate and its preparation method and application, the intermediate is respectively provided with chemical structure shown in formula VI, formula VII:
Description
Technical field
The present invention relates to cangrelor intermediates and its preparation method and application, belong to chemicals synthesis technical field.
Background technique
Cangrelor be by AstraZeneca development, authorize the invertibity P2Y12 of The Medicines Company exploitation by
Body antagonist has the characteristics that rapid-action, half-life short, is a kind of ideal vein antiplatelet drug, and prevention heart coronaries are dynamic
Harmful blood clot is formed in arteries and veins, for acute thrombus such as percutaneous coronary intervention (pci) and acute coronary syndromes
Potentiality prevention.On June 22nd, 2015, cangrelor was ratified to list through FDA, and preparation specification is 50mg freeze drying powder injection, trade name
Kengreal.The molecular formula of cangrelor are as follows: C17H21Cl2F3N5Na4O12P3S2, molecular weight are as follows: and 864.286, No. CAS are as follows:
163706-36-3, chemical structural formula are as follows:
TEPAD, Chinese are as follows: N- [2- (first mercapto) ethyl] -2- [(3,3,3- trifluoro propyl) sulfydryl] -5 '-adenosines,
No. CAS are as follows: 163706-58-9, molecular formula are as follows: C16H22F3N5O4S2, molecular weight are as follows: and 469.11, chemical structural formula are as follows:
The compound is the key intermediate for synthesizing cangrelor, at present cangrelor
Preparation is usually all first to synthesize TEPAD using certain process route, and TEPAD is then carried out subsequent synthesis, and bank is finally made
The cangrelor synthetic route reported in Gray Lip river, such as document (J.Med.Chem.1999,42,213-220):
It is reported at present about the synthesis of TEPAD, is mainly the following synthetic route:
1) development company The Medicines Company disclose TEPAD synthetic route (J.Med.Chem.1999,
42,213-220), the wherein synthesized reference of compound 3 document (Chem.Pharm.Bull.25 (8) 1959-1969 (1977))
Preparation method:
The route, through peroxidating, hydrolysis, cyclization and reduction reaction, obtains 3 (adenosine-of compound using adenosine as raw material
2- thioketones), then compound 3 obtains TEPAD by nucleophilic displacement of fluorine, acetylation, substitution and hydrolysis.Step in this route
Rapid 1 and 2 in prepare compound 1 and 2, there is a large amount of water in reaction system, and water removing is had certain operation difficulty when post-processing；
Step 3 needs to generate in autoclave high temperature reaction under high pressure, and uses hypertoxic solvent carbon disulfide, can generate a large amount of waste liquids with
And H2S gas pollutes environment；And the route needs 7 steps to react altogether, and route is longer, and complicated operation, and from step 4 to step
Rapid 7, the total recovery of this several step is lower, and only 15~20%；Therefore, in general, which is not suitable for industrialized production.
2) document (fine-chemical intermediate 2013.30 (7), P 835-840) and document (Journal of Medicinal
Chemistry；vol.42；2；(1999)；P.213-220 the synthetic route of TEPAD is disclosed in):
The route is using guanosine as raw material, and through acetylation, chlorination, diazonium, nucleophilic and deprotection reaction, totally 5 steps are reacted
TEPAD is prepared, although process route is shorter, in the diazo-reaction of step 3, uses and largely crosses thioetherification conjunction
Object, this is crossed sulfide compound and synthesizes more difficult, higher cost, and the process route yield is lower, and total recovery only has 15~20%；Cause
This, in general, which is not suitable for industrialized production.
3) Chinese patent CN105061431 discloses the synthetic route of TEPAD:
The route is anti-by 9 step such as nucleophilic, nitrification, substitution, reduction, nucleophilic, cyclization using 2- thiobarbituricacidα- as raw material
TEPAD should be prepared, route is longer, and overall yield is lower；The raw material 2- thiobarbituricacidα- used in the route belongs to pipe
Class article processed, is unable to large-scale use；The substitution reaction of nitration reaction, ammonia that route is related to, hydrogenation reduction risk
It is larger；And multistep reaction is reacted in a manner of crude product in the route, is unfavorable for the quality control of final products；Therefore, always
For body, which is also not suitable for industrialized production.
4) Chinese patent CN201510881033 discloses the synthetic route of TEPAD:
The route is using compound II as starting material, by 6 step such as ammonification, nucleophilic, reduction, cyclization, nucleophilic and substitution
TEPAD is prepared in reaction, although this route is 45% according to its total recovery is described in patent, its multistep reaction is oily
Object is closed, the quality control for being unfavorable for intermediate is produced with amplification；Starting material compound II is not commercialized mass production, is not easy to obtain,
Higher cost；And being related to ammonolysis and nitro-reduction reaction is sealing system reaction under high pressure, and risk is larger；Therefore, always
For body, which is still not suitable for industrialized production.
Summary of the invention
In view of the above-mentioned problems existing in the prior art, the object of the present invention is to provide the intermediates for being used to prepare cangrelor
And preparation method thereof and the intermediate cangrelor preparation in application, to meet the industrialized production need of cangrelor
It asks.
For achieving the above object, The technical solution adopted by the invention is as follows:
A kind of cangrelor intermediate has chemical structure shown in formula VI:
A kind of method of cangrelor intermediate shown in preparation formula VI, including react as follows:
A) II compound of formula (i.e. guanosine) is left in alkali reacts to obtain with acetylizing agent III compound of formula；
B) III compound of formula reacts to obtain IV compound of formula with chlorination reagent in the presence of acid binding agent, catalyst；
C) IV compound of formula carries out diazo-reaction and obtains V compound of formula；
D) V compound of formula is left in alkali and reacts to obtain VI compound of formula with 2- (methyl mercapto) ethamine；
Its specific reaction route is as follows:
Alkali in a reaction is preferably organic base, and the organic base can be selected from N-methylmorpholine, triethylamine or diisopropyl second
Base amine.
Acetylizing agent in a reaction is preferably acetic anhydride.
Reaction dissolvent in a reaction is preferably at least one of methylene chloride, chloroform, acetonitrile, DMF, THF.
The molar ratio of acetylizing agent and II compound of formula in a reaction is preferably 1:1~5:1.
The reaction temperature of a reaction is preferably 0~30 DEG C, and further preferably 20~30 DEG C, the reaction time is preferably 1~5
Hour.
The acylation catalyst of catalytic amount, the preferred DMAP of acylation catalyst are added in a reaction.
Acid binding agent in b reaction is preferably triethylamine, diisopropyl ethyl amine, N, accelerine or N- methyl
Quinoline.
Catalyst in b reaction is preferably tetra-alkyl ammonium chloride, such as: tetramethyl ammonium chloride, tetraethyl ammonium chloride, four fourths
Ammonium chloride.
Chlorination reagent in b reaction is preferably phosphorus oxychloride.
Reaction dissolvent in b reaction is preferably at least one of DMF, acetonitrile, methylene chloride, chloroform, toluene.
The molar ratio of chlorination reagent and III compound of formula in b reaction is preferably 1:1~5:1.
The reaction temperature of b reaction is preferably 55~85 DEG C, and further preferably 75~85 DEG C, the reaction time is preferably 1~5
Hour.
To in b reaction the crude product good solvent that is reacted with chlorination reagent of III compound of formula and poor solvent mix
The sterling of IV compound of formula, the good solvent ethyl acetate, methylene chloride, second can be obtained in bonding solvent system after purification
Nitrile, methanol or ethyl alcohol, the preferred normal heptane of the poor solvent, isooctane or petroleum ether.
The reaction system of diazo-reaction is preferably nitrite-hydrochloric acid-stannous chloride or nitrous acid ester-three in c reaction
Methylchlorosilane, the preferred sodium nitrite of nitrite, the preferred isoamyl nitrite of the nitrous acid ester or the tertiary fourth of nitrous acid
Ester.
The reaction temperature of c reaction is preferably -15~55 DEG C, and further preferably 0~5 DEG C, the reaction time is preferably 1~5
Hour.
The mixed solvent system of crude product good solvent and poor solvent terminated to diazo-reaction in c reaction is pure
The sterling of V compound of formula, the good solvent ethyl acetate, methylene chloride, methyl tertiary butyl ether(MTBE) or first can be obtained after change
Benzene, the preferred normal heptane of the poor solvent, isooctane or petroleum ether.
Alkali in d reaction is preferably organic base or inorganic base, the preferred triethylamine of the organic base or diisopropyl ethyl amine,
Described inorganic base preferred carbonate, such as potassium carbonate, sodium carbonate etc..
Reaction dissolvent in d reaction is preferably at least one of acetonitrile, DMF, DMSO, toluene, THF.
The molar ratio of 2- (methyl mercapto) ethamine and V compound of formula in d reaction is preferably 1:1~2:1.
The reaction temperature of d reaction is preferably 60~100 DEG C, and further preferably 70~80 DEG C, the reaction time is preferably 1~
5 hours.
Another cangrelor intermediate has chemical structure shown in formula VII:
A kind of method of cangrelor intermediate shown in preparation formula VII, alkaline hydrolysis obtains VI compound of formula under alkaline condition
VII compound of formula, reaction equation are as follows:
Alkaline condition in reaction is preferably formed by inorganic base, and sodium hydroxide or potassium hydroxide can be selected in the inorganic base.
Alkaline hydrolysis solvent for use in reaction is preferably at least one of methanol, tetrahydrofuran.
Reaction temperature is preferably 20~30 DEG C.
A kind of application of cangrelor intermediate shown in formula VII is to leave VII compound of formula and 3,3,3- trifluoros in alkali
I intermediate of known formula of cangrelor is made in propyl thiol reaction, and reaction equation is as follows:
Alkali in reaction is preferably organic base or inorganic base, the organic base be preferably sodium methoxide, potassium methoxide, sodium ethoxide,
Potassium ethoxide, sodium tert-butoxide or potassium tert-butoxide, further preferred sodium methoxide or sodium tert-butoxide, the preferred sodium hydroxide of the inorganic base,
Potassium hydroxide or sodium hydrogen, further preferred sodium hydroxide or sodium hydrogen.
Reaction dissolvent in reaction is preferably at least one of DMF, DMSO, toluene, NMP.
The molar ratio of 3,3,3- trifluoro propyl mercaptan and VII compound of formula is preferably 1:1~2:1 in reaction.
The reaction temperature of reaction is preferably 60~100 DEG C, and further preferably 70~80 DEG C, the reaction time is preferably 1~5
Hour.
I intermediate of known formula (i.e. TEPAD) of prepared cangrelor can be used to subsequent bank lattice according to the prior art
The preparation of Lei Luo.
Compared with prior art, the present invention have following conspicuousness the utility model has the advantages that
1) intermediate formula VI provided by the present invention, VII compound of formula are applied, the known key for synthesizing cangrelor can be made
The preparation process of intermediate TEPAD (i.e. type I compound) is simple, and cost reduces, and quality is easy to control, and high income (is changed from formula II
Object is closed to type I compound, 35%) the total moles yield of entire synthetic route is greater than, be conducive to the preparation of cangrelor；
2) preparation of intermediate formula VI provided by, VII compound of formula, easy to operate, intermediate product is easy to purify, quality
Controllability is strong, and products obtained therefrom purity is high, agents useful for same is cheap and easy to get, while toxic or hazardous agents are not used, safety non-pollution,
Also be not used the reagent of the high requirements on the equipment such as strong corrosive reagent, at the same the reaction of entire route all under normal conditions into
Row does not have any particular/special requirement, production cost to equipment without high temperature and pressure operation (reaction temperature is integrally no more than 100 DEG C)
It is low.
In short, the present invention utilizes raw material (II compound of formula, i.e. guanosine) cheap and easy to get, cangrelor intermediate formula is synthesized
VI, formula VII and type I compound (TEPAD) have total moles high income, easy to operate, safety non-pollution, want to equipment without special
It asks, the advantages such as production cost is low, there is extremely strong practical value to the industrialization for realizing cangrelor, have compared with the existing technology
There is conspicuousness progress.
Specific embodiment
Technical solution of the present invention is described in further detail and completely below with reference to embodiment and comparative example.
Embodiment 1:
The preparation of compound III (2', 3', 5'- triacetyl guanosine):
Acetic anhydride (150g, 1.45mol) is added dropwise to containing compound ii (i.e. guanosine, 100g, 0.35mol), N- methyl
Morpholine (180g, 1.8mol), DMAP (4.3g, 0.035mol) acetonitrile (800mL) solution in, after being added dropwise, reaction solution exists
It is reacted 2 hours at 20~30 DEG C, reaction was completed, and reaction solution is concentrated under reduced pressure into no solution and distillates, and ethyl alcohol is added in residual solution
(200mL) is recrystallized, and is filtered, and filter cake is in 45~55 DEG C of drying to get compound III (2', 3', 5'- triacetyl guanosine):
125g, molar yield 86.8%.
After tested: ESI-MS:[M+H]+=410.1.
Embodiment 2:
The system of compounds Ⅳ (9- [tri--o- acetyl group-beta-d- ribofuranose of 2,3,5-] -2- amido-6-chloropurine)
It is standby:
Phosphorus oxychloride (180g, 1.12mol) is added dropwise to containing compound III (100g, 0.234mol), tetraethyl chlorination
Ammonium (80g, 0.48mol), triethylamine (24g, 0.244mol) toluene (800mL) solution in, after being added dropwise, reaction solution heating
It is reacted two hours to 75~85 DEG C of insulated and stirreds, reaction was completed, adds water quenching reaction, and ethyl acetate (800mL) extraction is then added
It takes, the organic phase isolated is washed with water twice, is then washed to system with 10wt% sodium bicarbonate aqueous solution in alkalescent, chlorination
Sodium water solution is washed once, and dry with anhydrous sodium sulfate, is filtered, is concentrated under reduced pressure into no solution and distillates, dichloro is added in residual solution
Methane (100mL) and normal heptane (400mL) are recrystallized, and are filtered, are obtained khaki solid matter, i.e., compounds Ⅳ (9- [2,3,
Tri--o- acetyl group-beta-d- ribofuranose of 5-] -2- amido-6-chloropurine): 87g, molar yield 82%.
After tested: ESI-MS:[M+H]+=428.2.
Embodiment 3:
The preparation of compound V (the chloro- 9- of 2,6- bis- (2', 3', 5'- tri--O- acetyl group-β-D-RIBOSE base) purine):
Isoamyl nitrite (165g, 1.41mol) is dissolved in methylene chloride (500mL) solution, then in 0~5 DEG C of item
Under part, it is added trim,ethylchlorosilane (76g, 0.70mol), is subsequently added into the DCM of compounds Ⅳ (100g, 0.234mol)
(500mL) solution is added dropwise in above-mentioned mother liquor, after charging, is continued under the conditions of the temperature and is stirred to react 1 hour, is terminated anti-
It answers, the sodium sulfite solution of saturation, liquid separation is added, the organic phase isolated successively uses sodium bicarbonate aqueous solution, saturated salt solution
Washing, and it is dry with anhydrous sodium sulfate, it filters, is concentrated under reduced pressure into no solution and distillates, methylene chloride (100mL) is added in residual solution
Recrystallized with normal heptane (350mL), filter, obtain yellow solid matter, i.e., compound V (2,6- bis- chloro- 9- (2', 3',
Tri--O- acetyl group-β of 5'--D-RIBOSE base) purine): 86g, molar yield 82%.
After tested: ESI-MS:[M+H]+=447.0.
Embodiment 4:
The preparation of compound 2- (methyl mercapto) ethamine:
Mercaptamine (113g, 1.0mol) is dissolved in ethyl alcohol (1.5L) solution, then under the conditions of -10~0 DEG C,
It is added sodium hydroxide (120g, 3.0mol), iodomethane (170g, 1.2mol) then is added dropwise, after being added dropwise, continues at the temperature
Under the conditions of be stirred to react 3 hours, reaction was completed, and partial solvent is evaporated off in low temperature backspin, and filtering, filtrate depressurizes at -0.09MPa
Distillation -0.09MPa collects 110~120 DEG C of fraction, obtains colourless oily mater, i.e. compound 2- (methyl mercapto) ethamine:
81g, molar yield 89%.
Embodiment 5:
The preparation of cangrelor midbody compound VI:
Compound V (80g, 0.18mol) is dissolved in acetonitrile (500mL) solution, change prepared by embodiment 4 is then added
Close object 2- (methyl mercapto) ethamine (32.5g, 0.36mol) and triethylamine (45.3g, 0.45mol), after charging, reaction solution liter
Temperature to 70~80 DEG C of insulated and stirreds are reacted 3 hours, and reaction was completed, and reaction solution is concentrated under reduced pressure into no solution and distillates, and adds in residual solution
Enter ethyl acetate (300mL) and water (200mL), liquid separation, the organic phase isolated is washed with sodium-chloride water solution, anhydrous sodium sulfate
It is dry, it filters, is concentrated under reduced pressure into no solution and distillates, obtain tan solid matter, i.e., cangrelor intermediate of the present invention
Object VI: 75g, molar yield 83% are closed, HPLC purity is 99.5%, by compound ii to cangrelor midbody compound VI
Four step total moles yields be 52.5%.
After tested:1HNMR(300MHz,CDCl3) δ 2.07 (s, 3H), 2.10~2.22 (m, 9H), 2.80 (t, J=
6.5Hz, 2H), 3.84 (s, 2H), 4.41 (dq, J=6.3,4.1,2.9Hz, 3H), 5.59 (dd, J=5.6,3.8Hz, 1H),
5.77 (t, J=5.5Hz, 1H), 6.16 (d, J=5.6Hz, 1H), 6.47 (s, 1H), 7.90 (s, 1H)；
ESI-MS:[M+H]+=502.05, [M+Na]+=524.00.
Embodiment 6:
The preparation of compound 3,3,3- trifluoro propanethiol:
(30mL second in the ethanol water of thiocarbamide (38g, 0.52mol) is added in trifluoro iodopropane (110g, 0.49mol)
Alcohol+1.5mL water), after charging, reaction solution is warming up to 90 DEG C of insulated and stirreds and reacts 5 hours, and reaction was completed, reaction solution cooling
To 0~5 DEG C, stirring, reaction solution solidification is filtered, and filter cake obtains white solid 90g in 45 DEG C of drying；
White solid is dissolved in water (150mL), be added 20wt% sodium hydrate aqueous solution, adjust solution pH be 12~
13, reaction solution back flow reaction 3 hours, reaction was completed, and reaction solution is cooled to room temperature, and adjusts pH to solution in acidity, distills, collect
55~58 DEG C of fraction is to get 3,3,3- trifluoro propanethiol of compound: 44g, and two step total moles yields are 65%.
Embodiment 7:
The preparation of cangrelor midbody compound VII:
Compound VI (15g, 0.03mol) is dissolved in methanol (50mL) solution, then under the conditions of 20~30 DEG C, is added
Water (100mL) solution of sodium hydroxide (4g, 0.1mol) after charging, continues under the conditions of the temperature that be stirred to react 1 small
When, reaction was completed, be added ethyl acetate (250mL) extraction, the organic phase isolated with anhydrous sodium sulfate it is dry after be spin-dried for get
Compound VII is directly used in and reacts in next step without purifying.
After tested:1HNMR(400MHz,DMSO-d6): 2.09 (s, 3H), 2.48~2.69 (m, 2H), 3.43~3.70 (m,
4H), 3.93 (q, J=3.8Hz, 1H), 4.02 (dd, J=13.1,6.9Hz, 1H), 4.12 (t, J=4.0Hz, 1H), 4.50 (t,
J=5.5Hz, 1H), 5.01~5.09 (m, 1H), 5.19 (s, 1H), 5.47 (s, 1H), 5.81 (d, J=5.9Hz, 1H), 8.40
(s,1H)；
ESI-MS:[M+H]+=375.95, [M+Na]+=398.00.
Embodiment 8:
The preparation of known key intermediate TEPAD, that is, chemical compounds I of cangrelor:
Sodium hydrogen (4.2g, 0.105mol) is added in DMF (30mL) solution, then under the conditions of 0~5 DEG C, is added and implements
3,3,3- trifluoro propanethiol (8g, 0.06mol) of compound prepared by example 6 keeps temperature to be stirred to react half an hour, and embodiment is added
DMF (20mL) solution of 7 gained compounds VII, after charging, it is small that reaction solution is warming up to 70~80 DEG C of insulated and stirred reactions 2.5
When, reaction was completed, and reaction solution is cooled to room temperature, and is added water (100mL), there is yellow solid precipitation, filters, filter cake ethyl alcohol
The mixed solution of (40mL) and water (30mL) is recrystallized, and the known key intermediate TEPAD to get cangrelor is filtered,
That is chemical compounds I: 9g, HPLC purity are 99.9%, by six steps of the known key intermediate TEPAD of compound ii to cangrelor
Total moles yield is 36.7%.
After tested:
TEPAD:1HNMRδ(500MHz,CD3OD): 8.27 (1H, s), 5.91 (1H, d, J=5.0Hz), 4.71~4.68
(1H, t, J=10.0Hz), 4.31~4.29 (1H, m), 4.13~4.11 (1H, m), 3.88~3.71 (4H, m), 3.31
(2H, m), 2.79~2.61 (4H, m), 2.14 (3H, s)；
ESI-MS:[M+H]+=470.05.
In conclusion the present invention synthesizes TEPAD by the preparation of midbody compound VI, VII, with document
(Journal of Medicinal Chemistry；vol.42；2；(1999)；P.213-220 it) compares, using identical initial
Raw material (guanosine) prepares TEPAD, and total moles yield is 36.7%, hence it is evident that is higher than document (Journal of Medicinal
Chemistry；vol.42；2；(1999)；P.213-220 15~20% in), and the present invention is by compound ii to compound
VI, VII again into the preparation process of TEPAD, and high-purity production can be obtained by simple solvent recrystallization in the intermediate product of preparation
Product, purifying is simple, quality controllable, avoids and brings unnecessary impurity in subsequent operation, is VI, VII and TEPAD's of compound
High-purity lays a solid foundation；Also, entire route is easy to operate, and to equipment without particular/special requirement, safety and environmental protection is produced into
This is low, is suitble to large-scale production.
Finally need indicated herein be: the above is only part preferred embodiments of the invention, should not be understood as to this hair
The limitation of bright protection scope, those skilled in the art's above content according to the present invention make it is some it is nonessential improvement and
Adjustment all belongs to the scope of protection of the present invention.
Claims (6)
1. a kind of preparation method of compound of formula I cangrelor intermediate, which is characterized in that the method comprises the following steps:
The first step
Second step
Third step
Wherein, in the first step, a) II compound of formula is left in alkali reacts to obtain with acetylizing agent III compound of formula；B) III chemical combination of formula
Object reacts to obtain IV compound of formula with chlorination reagent in the presence of acid binding agent, catalyst；C) it is anti-to carry out diazotising for IV compound of formula
It should obtain V compound of formula；D) V compound of formula is left in alkali and reacts to obtain VI compound of formula with 2- (methyl mercapto) ethamine；
Wherein, in second step, by VI compound of formula, alkaline hydrolysis obtains VII compound of formula under alkaline condition；
Wherein, in third step, VII compound of formula is left and 3,3,3- trifluoro propyl thiol reactions, obtained type I compound in alkali.
2. according to the method described in claim 1, it is characterized by: the alkali in a reaction is selected from wherein in the first step: organic base,
The organic base is selected from: N-methylmorpholine, triethylamine or diisopropyl ethyl amine；Acetylizing agent in a reaction is selected from: acetic acid
Acid anhydride.
3. according to the method described in claim 1, it is characterized by: the acid binding agent in b reaction is selected from: three wherein in the first step
Ethamine, diisopropyl ethyl amine, N, accelerine or N-methylmorpholine；Catalyst in b reaction is selected from: tetraalkyl chlorination
Ammonium；Chlorination reagent in b reaction is selected from: phosphorus oxychloride.
4. according to the method described in claim 1, it is characterized by: wherein in the first step, diazo-reaction in c reaction it is anti-
Answering system is nitrite-hydrochloric acid-stannous chloride or nitrous acid ester-trim,ethylchlorosilane.
5. according to the method described in claim 1, it is characterized by: the alkali in d reaction is selected from: organic base wherein in the first step
Or inorganic base, the organic base are selected from: triethylamine or diisopropyl ethyl amine, the inorganic base are selected from: carbonate.
6. according to the method described in claim 1, it is characterized by: the alkali is selected from wherein in third step: organic base is inorganic
Alkali, the organic base are selected from: sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide or potassium tert-butoxide, the inorganic base choosing
From: sodium hydroxide, potassium hydroxide or sodium hydrogen.
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