CN107001405B - The method for preparing cangrelor intermediate - Google Patents
The method for preparing cangrelor intermediate Download PDFInfo
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- CN107001405B CN107001405B CN201680003950.7A CN201680003950A CN107001405B CN 107001405 B CN107001405 B CN 107001405B CN 201680003950 A CN201680003950 A CN 201680003950A CN 107001405 B CN107001405 B CN 107001405B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to the methods for preparing cangrelor intermediate.Specifically, the present invention relates to the method for preparing cangrelor intermediate (I), the method includes the step of by 2- haloadenine nucleosides (XI) and 3,3,3- trifluoro propyl sulfide (VI) are reacted.The cost of the preparation method is low, easy to operate, is easily isolated purifying, and yield is high, is suitable for being mass produced.
Description
Technical field
The present invention relates to the preparation methods of cangrelor intermediate, the in particular to side of the reduction of imine intermediate carboxylate
Method.
Background technique
Cangrelor (A) (N- [2- (methyl mercapto) ethyl] -2- [(3,3,3- trifluoro propyl) is thio] -5 ' adenylate bands (two
Chlorine methylene) tetra-na diphosphate salt single acid anhydride) be Adenosine diphosphate sweet (ADP) receptor P2Y12 inhibitor, by inhibit gland it is sweet
Cyclase Activity, reaches inhibition platelet aggregation, and indication is in percutaneous arterial Interventional Therapy and artery syndrome,
Prevent thrombosis.
The synthetic method of cangrelor is described in the prior art (ZL94191559.X), comprising the following steps:
1), passed through with adenosine -2- thioketones (2- sulfydryl adenosine) (XI) and chloro- 1,1,1- trifluoro propane (XII) of 3- for raw material
Substitution reaction obtains cangrelor intermediate (V);
2), cangrelor intermediate (V) under the conditions of sodium acetate and acetic anhydride, protect to obtain in cangrelor by upper acetyl group
Mesosome (IV);
3), cangrelor intermediate (IV) reacts to obtain cangrelor with 2- iodoethyl Dimethyl sulfide under the conditions of sodium hydride
Intermediate (II);
4), cangrelor intermediate (II) is obtained among cangrelor in methanol solvate with sodium hydroxide deacetylate
Body (I).
The disadvantages of this method are: adenosine -2- thioketones (2- sulfydryl adenosine) synthesis difficulty is big and needs to use carbon disulfide gas
Body, not only the high requirements on the equipment, also as odor pollution environment, keeps its cost very high, and adenosine -2- thioketones (2- sulfydryl gland
Glycosides) and chloro- 1,1,1- trifluoro propane reaction condition of 3- it is harsher, product needed column purification, low yield.
Summary of the invention
For overcome the deficiencies in the prior art, it is prepared in cangrelor the present invention provides a kind of simple, economical, safety
The cost of the method for mesosome, this method is low, easy to operate, is easily isolated purifying, and yield is high, is suitable for industrialization large-scale production.
One aspect of the present invention provides a kind of formula (XI) compound represented,
Wherein X is F, Cl, Br or I;R7For hydrogen orR8For hydrogen or R5;R9For hydrogen or R2;R10For hydrogen or R3;
R11For hydrogen or R4;R2、R3、R4、R5The respectively protecting group of hydroxyl or amino.
Further, compound (XI) preferably is selected from following compound:
Wherein X, R2、R3、R4、R5As previously described.
Formula (XI) compound represented is applied to prepare cangrelor in which can be convenient.
Another aspect of the present invention is related to the method for Formula (XII),
The described method includes :-trifluoro propyl sulfide (VI) is in the presence of alkaline medium by compound (XI) and 3,3,3
The step of reaction,
Wherein X is F, Cl, Br or I;R7For hydrogen orR8For hydrogen or R5;R9For hydrogen or R2;R10For hydrogen or R3;
R11For hydrogen or R4;R2、R3、R4、R5The respectively protecting group of hydroxyl or amino;R1For hydrogen, alkyl, aryl, alkyl acyl, aryl acyl
Base ,-S-R12, wherein the alkyl, aryl, alkyl acyl, aryl-acyl are optionally substituted base substitution;R12For optionally by
The alkyl or aryl that substituent group replaces.
Further, the present invention relates to the preparation method of cangrelor intermediate (I),
The described method includes:
Method (1): with 2- haloadenine nucleosides (VII) and 3,3,3- trifluoro propyl sulfide (VI) are raw material, are passed through
Substitution reaction obtains cangrelor intermediate (V), then protects the hydroxyl of intermediate (V) and amino to obtain Kan Ge with protecting group
Thunder Lip river intermediate (IV), intermediate (IV) replace Ethyl methyl sulfide (III) progress substitution reaction to obtain cangrelor with 2- again
Intermediate (II), cangrelor intermediate (II) slough protecting group and obtain cangrelor intermediate (I).
Method (2): the hydroxyl of 2- haloadenine nucleosides (VII) and amino are protected to obtain in cangrelor with protecting group
Mesosome (VIII), cangrelor intermediate (VIII) and 3,3,3- trifluoro propyl sulfide (VI) obtain Kan Ge by substitution reaction
Thunder Lip river intermediate (IV), intermediate (IV) replace Ethyl methyl sulfide (III) progress substitution reaction to obtain cangrelor with 2- again
Intermediate (II), cangrelor intermediate (II) slough protecting group and obtain cangrelor intermediate (I).
Method (3): 2- haloadenine nucleosides (VII) being protected to obtain cangrelor intermediate (VIII) with protecting group,
Cangrelor intermediate (VIII) and 2- replace Ethyl methyl sulfide (III) Dai Fanying to obtain cangrelor intermediate (IX), bank
For Gray Lip river intermediate (IX) again with 3,3,3- trifluoro propyl sulfide (VI) obtain cangrelor intermediate by substitution reaction
(II), cangrelor intermediate (II) sloughs protecting group and obtains cangrelor intermediate (I).
Method (1) specifically comprises the following steps:
1) under alkaline condition, with 2- haloadenine nucleosides (VII) and 3,3,3- trifluoro propyl sulfide (VI) are raw material,
Cangrelor intermediate (V) is obtained by substitution reaction;In the 2- haloadenine nucleosides (VII) X be selected from F, Cl, Br or
I;R in sulfide (VI)1For hydrogen, alkyl, aryl, alkyl acyl, aryl-acyl ,-S-R12, wherein the alkyl, aryl, alkyl
Acyl group, aryl-acyl are optionally substituted base substitution;R12For the alkyl or aryl for being optionally substituted base substitution;It is preferred that 3,3,3-
Trifluoro propyl thiolacetic acid ester.The alkaline medium is sodium hydride, hydrofining, sodium carbonate, potassium carbonate, cesium carbonate, hydroxide
Potassium, lithium hydroxide, sodium hydroxide, potassium tert-butoxide;It is preferred that potassium carbonate.The reaction dissolvent be water, methanol, ethyl alcohol, isopropanol,
N-butanol, isobutanol, the tert-butyl alcohol, acetonitrile, tetrahydrofuran, n,N-Dimethylformamide or n,N-dimethylacetamide it is any
Or combinations thereof;It is preferred that n,N-Dimethylformamide.The reaction is carried out in temperature at 0-100 DEG C;It is preferred that 80 ± 5 DEG C of progress.
2) it protects protecting group on cangrelor intermediate (V) to obtain cangrelor intermediate (IV);The protecting group:
R2、R3、R4、R5The respectively protecting group of hydroxyl or amino;It is preferred that acetyl group.
3) under alkaline condition, cangrelor intermediate (IV) replaces Ethyl methyl sulfide (III) to be replaced with 2- again
Reaction obtains cangrelor intermediate (II).The 2- replaces Ethyl methyl sulfide to be middle R6Selected from F, Cl, Br, I, methylsulfonyl
Base, benzenesulfonyl or substitution benzenesulfonyl;It is preferred that 2- bromoethyl Dimethyl sulfide.The alkaline medium are as follows: sodium hydride, hydrogenation
Potassium, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium tert-butoxide;It is preferred that potassium carbonate.Described
Reaction dissolvent is: methanol, ethyl alcohol, acetonitrile, tetrahydrofuran or n,N-Dimethylformamide it is any or combinations thereof;It is preferred that N, N-
Dimethylformamide.The reaction is carried out in temperature at 0-100 DEG C;It is preferred that 30 ± 5 DEG C of progress.
4) cangrelor intermediate (II) is sloughed into protecting group and obtains cangrelor intermediate (I).
Method (2) specifically comprises the following steps:
1) it protects protecting group on 2- haloadenine nucleosides (VII) to obtain cangrelor intermediate (VIII).Described
X is selected from F, Cl, Br or I in 2- haloadenine nucleosides (VII);The protecting group: R2、R3、R4、R5Respectively hydroxyl or ammonia
The protecting group of base;It is preferred that acetyl group.
2) under alkaline condition, cangrelor intermediate (VIII) and 3,3,3 ,-trifluoro propyl sulfide (VI) is by taking
Generation reaction obtains cangrelor intermediate (IV).R in the sulfide (VI)1For hydrogen, alkyl, aryl, alkyl acyl, aryl
Acyl group ,-S-R12, wherein the alkyl, aryl, alkyl acyl, aryl-acyl are optionally substituted base substitution;R12For optionally
The alkyl or aryl being substituted with a substituent;It is preferred that 3,3,3- trifluoro propyl thiolacetic acid esters.The alkaline medium be sodium hydride,
Hydrofining, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium tert-butoxide;It is preferred that potassium carbonate.Institute
The reaction dissolvent stated is water, methanol, ethyl alcohol, isopropanol, n-butanol, isobutanol, the tert-butyl alcohol, acetonitrile, tetrahydrofuran, N, N- diformazan
Base formamide or n,N-dimethylacetamide it is any or combinations thereof;It is preferred that n,N-Dimethylformamide.The reaction exists
Temperature is carried out at 0-100 DEG C;It is preferred that 80 ± 5 DEG C of progress.
3) under alkaline condition, cangrelor intermediate (IV) replaces Ethyl methyl sulfide (III) to be replaced with 2- again
Reaction obtains cangrelor intermediate (II).The 2- replaces Ethyl methyl sulfide to be middle R6Selected from F, Cl, Br, I, methylsulfonyl
Base, benzenesulfonyl or substitution benzenesulfonyl;It is preferred that 2- bromoethyl Dimethyl sulfide.The alkaline medium are as follows: sodium hydride, hydrogenation
Potassium, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium tert-butoxide;It is preferred that potassium carbonate.Described
Reaction dissolvent is: methanol, ethyl alcohol, acetonitrile, tetrahydrofuran or n,N-Dimethylformamide it is any or combinations thereof;It is preferred that N, N-
Dimethylformamide.The reaction is carried out in temperature at 0-100 DEG C;It is preferred that 30 ± 5 DEG C of progress.
4) cangrelor intermediate (II) is sloughed into protecting group and obtains cangrelor intermediate (I).
Method (3) specifically comprises the following steps:
1) under alkaline condition, cangrelor intermediate (VIII) and 2- replace Ethyl methyl sulfide (III) to pass through substitution
Reaction obtains cangrelor intermediate (IX).X is selected from F, Cl, Br or I in the 2- haloadenine nucleosides (VII);It is described
Protecting group: R2、R3、R4、R5The respectively protecting group of hydroxyl or amino;It is preferred that acetyl group.
2) under alkaline condition, cangrelor intermediate (VIII) and 2- replace Ethyl methyl sulfide (III) to pass through substitution
Reaction obtains cangrelor intermediate (IX).The 2- replace Ethyl methyl sulfide be in middle R6Selected from F, Cl, Br, I, methylsulphur
Acyl group, benzenesulfonyl or substitution benzenesulfonyl;It is preferred that 2- bromoethyl Dimethyl sulfide.The alkaline medium are as follows: hydrogen
Change sodium, hydrofining, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium tert-butoxide;It is preferred that carbonic acid
Potassium.The reaction dissolvent is: any or its group of methanol, ethyl alcohol, acetonitrile, tetrahydrofuran or n,N-Dimethylformamide
It closes;It is preferred that n,N-Dimethylformamide.The reaction is carried out in temperature at 0-100 DEG C;It is preferred that 30 ± 5 DEG C of progress.
3) under alkaline condition, again with 3,3,3 ,-trifluoro propyl sulfide (VI) is taken cangrelor intermediate (IX)
Generation reaction obtains cangrelor intermediate (II).R in the sulfide (VI)1For hydrogen, alkyl, aryl, alkyl acyl, aryl
Acyl group ,-S-R12, wherein the alkyl, aryl, alkyl acyl, aryl-acyl are optionally substituted base substitution;R12For optionally
The alkyl or aryl being substituted with a substituent;;It is preferred that 3,3,3- trifluoro propyl thiolacetic acid esters.The alkaline medium is hydrogenation
Sodium, hydrofining, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium tert-butoxide;It is preferred that carbonic acid
Potassium.The reaction dissolvent is water, methanol, ethyl alcohol, isopropanol, n-butanol, isobutanol, the tert-butyl alcohol, acetonitrile, tetrahydrofuran, N,
Dinethylformamide or n,N-dimethylacetamide it is any or combinations thereof;It is preferred that n,N-Dimethylformamide.Described
Reaction is carried out in temperature at 0-100 DEG C;It is preferred that 80 ± 5 DEG C of progress.
4) cangrelor intermediate (II) is sloughed into protecting group and obtains cangrelor intermediate (I).
The method yield of above-mentioned three kinds of methods compared with the prior art has to be improved significantly, and has easy to operate, production
Product such as are easily isolated and purify at the advantages.In addition, it has been found that the amplification using above-mentioned three kinds of methods in industrially scalable is prepared in fact
In testing, method (1) decreases with yield of the method (3) in amplification process, and the yield of method (2) does not reduce substantially, and
And product purity is high, more easily separated and purifying is more applicable for industrialized production.
Further, the invention further relates to the preparation methods of cangrelor (A), and the method includes intermediate (I), intermediates
(XIII), intermediate (XIV) prepares cangrelor (A).
Specifically comprise the following steps:
5) cangrelor intermediate (I) obtains cangrelor intermediate in triethyl phosphate solvent with phosphorus oxychloride reaction
(XIII)。
5) cangrelor intermediate (XIII) is reacting to obtain cangrelor reactive intermediate (XIV) with CDI, and activity is intermediate
Body (XIV) directly bends acid of seeing with chlorine and reacts to obtain cangrelor (A).
The method of the present invention has synthetic route short, easy to operate, is easily isolated and purifies, and solvent usage is few, at low cost, peace
The features such as complete and suitable industrialized production, has significant Social benefit and economic benefit.
" alkyl " refers to the aliphatic hydrocarbon group of saturation, straight chain and branched group including 1 to 20 carbon atom.Preferably comprise 1
To the alkyl of 10 carbon atoms, such as methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl group, tert-butyl or amyl etc..More
Low alkyl group preferably containing 1 to 6 carbon atom, for example, methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl group or
Tert-butyl, amyl, heptyl etc..Alkyl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more
A following group, independently selected from alkoxy, halogen, hydroxyl, nitro, cyano, naphthenic base, heterocycle, aryl, heteroaryl, carbonyl
Base.
" aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared to adjoin
The ring of carbon atom pair) group, preferably 6 to 10 yuan of aryl, more preferable phenyl and naphthalene, most preferably phenyl.Aryl can be
Substituted or unsubstituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkyl, alkene
Base, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl,
Heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
Alkyl ,-C (O) alkene that " acyl group " refers to and replace including group-C (O) H ,-C (O) alkyl ,-C (O)
The cycloalkanes that alkynyl ,-C (O) naphthenic base ,-C (O) that base, the alkenyl of-C (O) substitution ,-C (O) alkynyl ,-C (O) replace replace
Heteroaryl ,-C (O) heterocycle and-C (O) that aryl that base ,-C (O) aryl ,-C (O) replace ,-C (O) heteroaryl ,-C (O) replace
Substituted heterocycle.
" hydroxyl protection base " is the group appropriate for hydroxyl protection known in the art, referring to document
(" Protective Groups in Organic Synthesis ", 5Th.Ed.T.W.Greene & P.G.M.Wuts) in
Hydroxy-protective group.As an example, preferably, the hydroxyl protection base can be (C1-10Alkyl or aryl)3Silylation, example
Such as: triethyl group silicon substrate, triisopropylsilyl, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate etc.;It can be C1-10Alkyl
Or replace alkyl, and such as: methyl, tert-butyl, allyl, benzyl, methoxy, ethoxyethyl group, 2- THP trtrahydropyranyl
(THP) etc.;It can be (C1-10Alkyl or aromatic radical) acyl group, such as: formoxyl, acetyl group, benzoyl etc.;It can be (C1-6
Alkyl or C6-10Aryl) sulfonyl;It is also possible to (C1-6Alkoxy or C6-10Aryloxy) carbonyl.
" amino protecting group " is the group appropriate for amido protecting known in the art, referring to document
(" Protective Groups in Organic Synthesis ", 5Th.Ed.T.W.Greene & P.G.M.Wuts) in
Amido protecting group, it is preferable that the amino protecting group can be (C1-10Alkyl or aromatic radical) acyl group, such as: formoxyl,
Acetyl group, benzoyl etc.;It can be (C1-6 alkyl or C6-10Aryl) sulfonyl;It is also possible to (C1-6Alkoxy or C6-10Virtue
Base oxygroup) carbonyl, Boc or Cbz.
Unless stated to the contrary, the english abbreviation used in the specification and in the claims has following meanings.
DMF:N, dinethylformamide
Ac2O: acetic anhydride
MeOH: methanol
POCl3: phosphorus oxychloride
(EtO)3PO: triethyl phosphate
K2CO3: potassium carbonate
AcONa: sodium acetate
NaOH: sodium hydride
CDI:N, N '-carbonyl dimidazoles
n-Bu3N: tri-n-butylamine
Specific embodiment
The present invention is explained in detail below with reference to specific example, so that this is more fully understood specially in those skilled in the art
Benefit, specific example are only used to illustrate the technical scheme of the present invention, and do not limit the present invention in any way.
Embodiment 1: cangrelor intermediate (I) is prepared
Step 1) prepares cangrelor intermediate (V)
By 2- chloroadenine nucleosides (VII) 20g (66.3mmol, 1.0eq), 3,3,3 ,-trifluoro propyl thiolacetic acid ester
(VI) 17.1g (99.5mmol, 1.5eq) is added in 200mlDMF, stirring and dissolving, and Anhydrous potassium carbonate 27.4g is added
(198.9mmol, 3.0eq).Three times by the displacement of reaction system nitrogen, it is small that it is heated to 80 ± 5 DEG C of reactions 8~10 under nitrogen protection
When.It is slightly cooling, it is concentrated under reduced pressure most of DMF, adds water 200ml, be extracted with ethyl acetate (200ml × 3), organic phase washing
(200ml × 2), saturated brine wash (200mL × 1), and anhydrous sodium sulfate is dry.Filtering, filtrate concentration is dry, with ethyl acetate and
Petroleum ether is recrystallized to give cangrelor intermediate (V) 24.9g (yellow solid) (yield 95%), HPLC purity 97%.
1HNMR:(DMSO-d6)
δ: 8.26 (s, 1H), 7.46 (br, 2H), 5.81~5.83 (d, 1H), 5.42~5.44 (d, 1H), 5.17~5.19
(d, 1H), 5.02~5.05 (t, 1H), 4.57~4.61 (q, 1H), 4.11~4.13 (q, 1H), 3.89~3.92 (q, 1H),
3.52~3.65 (m, 2H), 3.19~3.29 (m, 2H), 2.68~2.76 (m, 2H).
MS (M+1): 396.09.
Step 2) prepares cangrelor intermediate (IV)
Cangrelor intermediate (V) 15g (38mmol, 1.0eq) is added in 120ml acetic anhydride, sodium acetate is added
2.2g (26.6mmol .0.7eq) is heated to 70 ± 5 DEG C under nitrogen protection and reacts 14~16 hours.It is cooled to room temperature, adds water
250ml is stirred 4 hours, is extracted with dichloromethane (200ml × 3), organic phase washs (200mL × 2), water with saturated sodium bicarbonate
It washes (200ml × 1), anhydrous sodium sulfate is dry.Filtering, filtrate concentration is dry to obtain cangrelor intermediate (IV) 19.3g (yellow bubble
Foam shape solid) (yield 90%), HPLC purity 80%.
1HNMR:(DMSO-d6)
δ: 10.87 (s, 1H), 8.55 (s, 1H), 6.24~6.26 (d, 1H), 5.96~5.99 (t, 1H), 5.56~5.59
(t, 1H), 4.37~4.40 (m, 2H), 4.25~4.28 (m, 3H), 3.31~3.33 (m, 2H), 2.80~2.84 (m, 2H),
2.24 (s, 3H), 2.12 (s, 3H), 2.04 (s, 3H), 2.00 (s, 3H).
MS (M+1): 564.12.
Step 3) prepares cangrelor intermediate (II)
By cangrelor intermediate (IV) 15g (26.6mmol, 1.0eq), Anhydrous potassium carbonate 7.4g (53.3mmol,
2.0eq) it is added in 75mLDMF, nitrogen is replaced three times, 2- bromoethyl Dimethyl sulfide (III) 6.2g (39.9mmol,
1.5eq), under nitrogen protection 30 ± 5 DEG C react 8~10 hours, add water 150ml, (150ml × 3) be extracted with ethyl acetate, have
Machine is mutually washed with water (150ml × 2), saturated salt solution (150ml × 1), and anhydrous sodium sulfate is dry.Filtering, filtrate concentration is dry to be obtained
Cangrelor intermediate (II) 16.9g (yellow oily) (yield 100%), HPLC purity 55%.
1HNMR:(DMSO-d6)
δ: 8.66 (s, 1H), 8.55 (s, 1H), 6.28~6.30 (d, 1H), 5.94~5.97 (t, 1H), 5.86~5.61
(t, 1H), 4.38~4.41 (m, 2H), 4.22~4.26 (m, 3H), 3.36~3.37 (m, 2H), 2.69~2.77 (m, 4H),
2.221 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H).
MS (M+1): 638.13.
Step 4) prepares cangrelor intermediate (I)
Cangrelor intermediate (II) 10g (15.7mmol, 1.0eq) is added in 50mL methanol, sodium hydroxide is added
3.8g (94.2mmol .6.0eq) is heated to 65 ± 5 DEG C under nitrogen protection and reacts 1~2 hour.It is cooled to room temperature, uses acetic acid
PH=6-8 is adjusted, dry methanol is concentrated, adds water 100ml, is extracted with ethyl acetate (100ml × 3), organic phase saturated sodium bicarbonate
It washs (100mL × 1), washes (100ml × 1), saturated common salt water washing (100ml × 1), anhydrous sodium sulfate is dry.Filtering, filter
Liquid concentration is dry, is recrystallized to give cangrelor intermediate (I) 5.2g (off-white powder) (yield 70%), HPLC with DMF and water
Purity 95%.
1HNMR:(DMSO-d6)
δ: 8.26 (s, 1H), 8.11 (br, 1H), 5.80~5.82 (d, 1H), 5.07~5.22 (m, 3H), 4.54~4.57
(t, 1H), 4.09~4.12 (m, 1H), 3.90~3.93 (m, 1H), 3.52~3.64 (m, 4H), 3.22~3.25 (m, 2H),
2.66~2.78 (m, 4H), 2.07 (s, 3H).
MS (M+1): 470.13.
Embodiment 2: cangrelor intermediate (I) (synthetic line 2) is prepared
Step 1) prepares cangrelor intermediate (VIII)
By 2- chloroadenine nucleosides (VII) 20g (66.3mmol, 1.0eq), sodium acetate 4.74g (66.3mmol, 1.0eq),
100ml acetic anhydride is added in 250ml single port bottle, stirring and dissolving, by reaction system nitrogen displacement three times, under nitrogen protection plus
Heat to 80 ± 5 DEG C react 8~10 hours.It is slightly cooling, it is concentrated under reduced pressure most of acetic anhydride, adds water 200ml, extracted with ethyl acetate
It takes (200ml × 3), organic phase washes (200ml × 2), and saturated brine washs (200mL × 1), and anhydrous sodium sulfate is dry.Filtering,
Filtrate concentration is dry to obtain cangrelor intermediate (VIII) 30g (white solid) (yield 99.3%), HPLC purity 96.3%.
MS (M+1): 470.09.
Step 2) prepares cangrelor intermediate (IV)
By cangrelor intermediate (VIII) 10g (21.3mmol, 1.0eq), 3,3,3 ,-trifluoro propyl thiolacetic acid ester
(VI) 7.3g (42.6mmol, 2.0eq), potassium carbonate 8.8g (61.9mmol, 3.0eq) are added in 100mlDMF, are protected in nitrogen
70 ± 5 DEG C are heated under shield to react 14~16 hours.It is cooled to room temperature, adds water 200ml, be extracted with ethyl acetate (200ml ×
3), organic phase is washed with water (200ml × 1), and it is dry that saturated sodium-chloride washs (200mL × 2) anhydrous sodium sulfate.Filtering, filtrate are dense
It contracts and dry obtains cangrelor intermediate (IV) 12g (yellow solid) (yield 100%), HPLC purity 93.7%.
MS (M+1): 564.13.
Step 3) prepares cangrelor intermediate (II)
By cangrelor intermediate (IV) 5g (8.9mmol, 1.0eq), Anhydrous potassium carbonate 2.5g (17.8mmol, 2.0eq)
It is added in 50mLDMF, nitrogen is replaced three times, 2- bromoethyl Dimethyl sulfide (III) 2.7g (17.8mmol, 2.0eq), in nitrogen
It is reacted 8~10 hours for 30 ± 5 DEG C under gas shielded, adds water 100ml, (100ml × 3) are extracted with ethyl acetate, organic phase is washed with water
(150ml × 2), saturated salt solution (150ml × 1), anhydrous sodium sulfate are dry.Filtering, filtrate concentration is dry to be obtained in cangrelor
Mesosome (II) 5.6g (yellow oily) (yield 100%), HPLC purity 95.2%.
MS (M+1): 638.16.
Step 4) prepares cangrelor intermediate (I)
Cangrelor intermediate (II) 5g (7.8mmol, 1.0eq) is added in 50mL methanol, sodium hydroxide is added
1.2g (31.2mmol, 4.0eq) is reacted at room temperature 3~5 hours under nitrogen protection.Add water 100ml, is extracted with ethyl acetate
(100ml × 3), organic phase are washed (100mL × 1) with saturated sodium bicarbonate, are washed (100ml × 1), saturated common salt water washing
(100ml × 1), anhydrous sodium sulfate are dry.Filtering, filtrate concentration is dry, is recrystallized to give bank Gray with methanol/ethyl acetate/water
Lip river intermediate (I) 2.7g (off-white powder) (yield 75%), HPLC purity 96.1%.
MS (M+1): 470.14.
Embodiment 3: cangrelor intermediate (I) (synthetic line 3) is prepared
Step 1) prepares cangrelor intermediate (VIII)
By 2- chloroadenine nucleosides (VII) 20g (66.3mmol, 1.0eq), sodium acetate 4.74g (66.3mmol, 1.0eq),
100ml acetic anhydride is added in 250ml single port bottle, stirring and dissolving, by reaction system nitrogen displacement three times, under nitrogen protection plus
Heat to 80 ± 5 DEG C react 8~10 hours.It is slightly cooling, it is concentrated under reduced pressure most of acetic anhydride, adds water 200ml, extracted with ethyl acetate
It takes (200ml × 3), organic phase washes (200ml × 2), and saturated brine washs (200mL × 1), and anhydrous sodium sulfate is dry.Filtering,
Filtrate concentration is dry to obtain cangrelor intermediate (VIII) 30g (white solid) (yield 99.3%), HPLC purity 97.1%.
MS (M+1): 470.10.
Step 2) prepares cangrelor intermediate (IX)
By cangrelor intermediate (VIII) 20g (42.6mmol, 1.0eq), Anhydrous potassium carbonate 11.8g (85.2mmol,
2.0eq) it is added in 50mLDMF, nitrogen is replaced three times, 2- bromoethyl Dimethyl sulfide (III) 13.1g (85.2mmol,
2.0eq), under nitrogen protection 30 ± 5 DEG C react 8~10 hours, add water 100ml, (100ml × 3) be extracted with ethyl acetate, have
Machine is mutually washed with water (150ml × 2), saturated salt solution (150ml × 1), and anhydrous sodium sulfate is dry.Filtering, filtrate concentration is dry to be obtained
Cangrelor intermediate (IX) 23.2g (yellow solid) (yield 100%), HPLC purity 70%.
MS (M+1): 544.13.
Step 3) prepares cangrelor intermediate (II)
By cangrelor intermediate (IX) 10g (18.4mmol, 1.0eq), 3,3,3 ,-trifluoro propyl thiolacetic acid ester (VI)
6.3g (36.8mmol, 2.0eq), potassium carbonate 5.1g (42.6mmol, 2.0eq) are added in 100mlDMF, under nitrogen protection
70 ± 5 DEG C are heated to react 14~16 hours.It is cooled to room temperature, adds water 200ml, (200ml × 3) are extracted with ethyl acetate, have
Machine is mutually washed with water (200ml × 1), and it is dry that saturated sodium-chloride washs (200mL × 2) anhydrous sodium sulfate.Filtering, filtrate concentration are done
To cangrelor intermediate (II) 11.8g (yellow oil) (yield 100%), HPLC purity 50%.
MS (M+1): 638.17.
Step 4) prepares cangrelor intermediate (I)
Cangrelor intermediate (II) 10g (15.6mmol, 1.0eq) is added in 50mL methanol, sodium hydroxide is added
2.4g (62.4mmol, 4.0eq) is reacted at room temperature 3~5 hours under nitrogen protection.Add water 200ml, is extracted with ethyl acetate
(200ml × 3), organic phase are washed (200mL × 1) with saturated sodium bicarbonate, are washed (200ml × 1), saturated common salt water washing
(200ml × 1), anhydrous sodium sulfate are dry.Filtering, filtrate concentration is dry, is recrystallized to give bank Gray with methanol/ethyl acetate/water
Lip river intermediate (I) 2.7g (off-white powder) (yield 37%), HPLC purity 93%.
MS (M+1): 470.13.
Embodiment 4: cangrelor (A) is prepared
Step 1) prepares cangrelor intermediate (XIII)
Cangrelor intermediate (I) 5g (10.6mmol, 1.0eq) is added in 50mL triethyl phosphate, is cooled to -5
~5 DEG C, be added phosphorus oxychloride 6.5g (42.4mmol, 4.0eq), in -5~5 DEG C react 4~5 hours, with ammonium hydroxide tune pH=8~
9, (100ml × 3) are extracted with methyl tertiary butyl ether(MTBE), hydrochloric acid tune pH=2~3 of water phase 1M analyse water phase in -5~5 DEG C of stirrings
It is brilliant.Filtering, filter cake are washed with water 10mL, are dried to obtain cangrelor intermediate (XIII) (white solid) 4.1g (yield
64.9%).
1HNMR:(DMSO-d6)
δ: 8.26 (s, 1H), 8.11 (br, 1H), 5.80~5.82 (d, 1H), 5.07~5.22 (m, 3H), 4.54~4.57
(t, 1H), 4.09~4.12 (m, 1H), 3.90~3.93 (m, 1H), 3.52~3.64 (m, 4H), 3.22~3.25 (m, 2H),
2.66~2.78 (m, 4H), 2.07 (s, 3H).
31P-NMR:(DMSO-d6)
δ: 0.006
MS (M+1): 550.07.
Step 2) prepares cangrelor (A)
Cangrelor intermediate (XIII) 2.0g (3.6mmol, 1.0eq) 10mL pyridinium dissolution, repeatedly n-butylamine 0.67g
(3.6mmol, 1.0eq) is stirred 10 minutes, and reduced pressure is dry to obtain yellow oil, this grease is molten with anhydrous DMF 30ml
Solution, be cooled to 0~5 DEG C of addition CDI 2.9g (18mmol, 5.0eq), add 0~5 DEG C be stirred to react 30 minutes after be warming up to room
Temperature reaction 4 hours is added methanol 0.9g (28.8mmol, 8.0eq) and stirs 30 minutes, and chlorine is added dropwise and bends sour tri-n-butylamine mono-salt of seeing
The 30mlDMF solution of 7.7g (18mmol, 5.0eq), drips and is stirred overnight at room temperature.Filtering, filtrate concentration is dry to obtain crude product, will
Crude product is purified with ion-exchange chromatography (DEAE- sephadex, 0M to 0.6M ammonium bicarbonate soln is as eluant, eluent)
Cangrelor ammonium salt solution is obtained, cangrelor ammonium salt solution is lyophilized to obtain cangrelor ammonium salt 2.5g, by cangrelor ammonium salt
Be dissolved in 20ml methanol, be added the sodium iodide acetone soln 300ml of 1M, stirring is precipitated solid, filtering, solid with acetone (3 ×
It 300ml) washs, obtains cangrelor tetrasodium salt 1.5g (yield 48%).
1HNMR:(D2O)
δ: 8.24 (s, 1H), 5.96~5.97 (d, 1H), 4.46~4.48 (m, 1H), 4.10~4.26 (m, 3H), 3.72
(s, 2H), 3.24~3.27 (m, 2H), 2.72~2.75 (m, 2H), 2.57~2.63 (m, 2H), 2.03 (s, 3H).
31P-NMR:(D2O)
δ: 8.38~8.49 (1P), 1.22~1.51 (1P), -10.13~-9.95 (1P).
MS (M+1): 775.93.
Due to describing the present invention according to its specific embodiment, certain modifications and equivalent variations are for being proficient in this neck
The technical staff in domain is obvious and is included within the scope of the invention.
Claims (9)
- Formula 1. (XI) compound represented,, which is characterized in that the compound is selected from:Wherein X is Cl.
- 2. a kind of method for preparing cangrelor intermediate (I),It is characterized by comprising the following steps:1) it protects protecting group on the hydroxyl and amino of 2- haloadenine nucleosides (VII) to obtain cangrelor intermediate (VIII),2) cangrelor intermediate (VIII) and 3,3,3- trifluoro propyl sulfide (VI) reaction obtain cangrelor intermediate (IV),3) cangrelor intermediate (IV) replaces Ethyl methyl sulfide (III) to react to obtain cangrelor intermediate (II) with 2- again,4) cangrelor intermediate (II) sloughs protecting group and obtains cangrelor intermediate (I),Wherein X is F, Cl, Br or I;R2、R3、R4For hydroxyl protection base, R5For amino protecting group;R1For C1-6Alkyl acyl;R6Choosing From F, Cl, Br, I.
- 3. the method according to claim 2 for preparing cangrelor intermediate (I), which is characterized in that in step 2), institute The reaction stated carries out under alkaline condition.
- 4. the method according to claim 3 for preparing cangrelor intermediate (I), which is characterized in that the alkaline medium Selected from sodium hydride, hydrofining, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium tert-butoxide.
- 5. the method according to claim 2 for preparing cangrelor intermediate (I), which is characterized in that in step 2), institute It states reaction to carry out in a solvent, the reaction dissolvent is selected from water, methanol, ethyl alcohol, isopropanol, n-butanol, isobutanol, tertiary fourth Alcohol, acetonitrile, tetrahydrofuran, N,N-dimethylformamide or DMAC N,N' dimethyl acetamide it is any or combinations thereof.
- 6. the method according to claim 2 for preparing cangrelor intermediate (I), which is characterized in that in step 3), institute The reaction stated carries out under alkaline condition.
- 7. the method according to claim 6 for preparing cangrelor intermediate (I), which is characterized in that the alkaline medium Selected from sodium hydride, hydrofining, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium tert-butoxide.
- 8. the method according to claim 2 for preparing cangrelor intermediate (I), which is characterized in that in step 3), institute It states reaction to carry out in a solvent, the reaction dissolvent is selected from methanol, ethyl alcohol, acetonitrile, tetrahydrofuran, N, N- dimethyl formyl Amine, N,N-dimethylformamide or dimethyl sulfoxide it is any or combinations thereof.
- 9. a kind of method for preparing cangrelor, including using method described in claim 2-8 any one to prepare bank Gray The step of the step of Lip river intermediate (I) and cangrelor intermediate (I) are prepared via a method which cangrelor
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