CN108658931A - A kind of preparation method of Raltitrexed key intermediate - Google Patents
A kind of preparation method of Raltitrexed key intermediate Download PDFInfo
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- CN108658931A CN108658931A CN201810230033.3A CN201810230033A CN108658931A CN 108658931 A CN108658931 A CN 108658931A CN 201810230033 A CN201810230033 A CN 201810230033A CN 108658931 A CN108658931 A CN 108658931A
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- NKTRJNZGFKLSGQ-AATRIKPKSA-N CC(C)(C)OC(N(C)C(/C=C/N1CCOCC1)=S)=O Chemical compound CC(C)(C)OC(N(C)C(/C=C/N1CCOCC1)=S)=O NKTRJNZGFKLSGQ-AATRIKPKSA-N 0.000 description 1
- BYVNRMCZMIIWMZ-BQYQJAHWSA-N CC(C)N(C(C)C)/C=C/C(N(C)C(C)=O)=S Chemical compound CC(C)N(C(C)C)/C=C/C(N(C)C(C)=O)=S BYVNRMCZMIIWMZ-BQYQJAHWSA-N 0.000 description 1
- GCXSXUXDRIAICD-UHFFFAOYSA-N C[BrH]CC(OCc1ccccc1)=O Chemical compound C[BrH]CC(OCc1ccccc1)=O GCXSXUXDRIAICD-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/38—Amides of thiocarboxylic acids
- C07C327/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C327/52—Y being a hydrogen or a carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/38—Amides of thiocarboxylic acids
- C07C327/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C327/54—Y being a hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- 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 invention discloses a kind of preparation methods of Raltitrexed intermediate formula (I) compound, using formula (IV) compound as starting material, in the presence of alkali, coupling ring-closure reaction occurs with halogen acetic acid ester, ester hydrolysis generates target product formula (I) compound later.The preparation method it is raw materials used it is cheap and easy to get, mild condition is easily controllable, high income, the three wastes are few, be conducive to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical fields, and in particular to a kind of preparation method of Raltitrexed intermediate.
Background technology
Raltitrexed is initially applied by Zeneca companies of Britain, takes the lead in listing in Britain in March, 1996, be tied for late period
The treatment of the carcinoma of the rectum (MCRC).Currently, Raltitrexed treatment colorectal cancer indication Australia, Argentina, bar
More than 20 a state approvals such as west, Canada, Singapore and EU member country.
In China, as socio-economic development, resident living mode change and the aggravation of aging of population, colorectal cancer
Ascendant trend year by year is presented in morbidity and mortality.First-line treatment drug of the Raltitrexed as advanced colorectal cancer, in China
Demand it is very big.
The synthetic method of the Raltitrexed of document report, 5- (methylamino) thiophene-2-carboxylic acids and its derivative are that it is crucial
Intermediate.As J.Med.Chem.1991,34,1594-1605 and patent US4992550 report the following synthesis side of the drug
Method：
Using 5- (tertbutyloxycarbonyl methylamino) thiophene -2-carboxylic acid as key intermediate, the preparation of the intermediate needs this method
Poisonous reagent iodomethane is used, needs to use expensive and dangerous positive fourth in the step of in addition thiazole ring 2 is introduced into carboxyl
Base lithium, severe reaction conditions, n-BuLi reaction need to carry out under -78 DEG C, anhydrous condition, and process dangerous is high, is unfavorable for work
Industry metaplasia is produced.
During patent CN201110001785.0 also discloses that one kind is with 5- (tertbutyloxycarbonyl methylamino) thiophene -2-carboxylic acid
The method of the synthesis Raltitrexed of mesosome：
The disadvantages of this method includes：1) it is nitrating agent to use fuming nitric aicd, generates a large amount of spent acid；2) iron powder reducing is used
Nitro generates a large amount of slag and effluents；3) high volatile poisonous reagent iodomethane is used, it is dangerous high.Disadvantage mentioned above limits it
Application in industrialized production.
Document Eur.J.Org.Chem.2000,1327-1334；Eur.J.Org.Chem.2000,3273-3278；
Synthesis, 2004, No.10, RR 1633-1640 reports the preparation method of 5- aminothiophene-2- carboxylic acid analogs：
It is repeatedly attempted through the present inventor, works as R1For alkyl, R2For amino protecting agent such as tert-butoxycarbonyl etc. whens, document item
Under part, the yield of target product is less than 20%, and by-product is more, is not readily separated purifying.
To sum up, the preparation method of Raltitrexed key intermediate is high in the prevalence of cost of material in the prior art, uses
Poisonous reagent, strong corrosive reagent, reaction step is tediously long, post-processing is seriously polluted, the dangerous high, technical problems such as yield is low.
The preparing technical field of the intermediate of antineoplastic Raltitrexed needs to develop that a kind of starting material is cheap and easy to get, mild condition is easy
In the few new technology route of control, high income, the three wastes.
Invention content
To achieve the above object, the present invention provides a kind of preparation methods of Raltitrexed intermediate formula (I) compound：
Include the following steps：
(1) formula (IV) compound and formula (III) compound carry out coupling and cyclization are anti-in organic solvent in the presence of a base
It should obtain formula (II) compound；
(2) ester hydrolysis reaction production (I) compound occurs for formula (II) compound.
Wherein,
R is amino protecting group, and the amino protecting group is selected from tertbutyloxycarbonyl, acetyl group, tablet held before the breast by officials methoxycarbonyl group, benzyloxy carbonyl
Base, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl etc..Preferably, R is tertbutyloxycarbonyl.
R1For-NR3R4, pyrrolidinyl, piperidyl or morpholinyl, wherein R3And R4It is separately alkyl；Preferably R3
And R4It is separately C1-C6Alkyl；Most preferably, R3And R4It is methyl.
X is halogen, selected from chlorine, bromine, iodine；Preferably, X is selected from bromine.
R2Selected from alkyl or benzyl.
Preferably, R2Selected from C1-C6Alkyl or benzyl.
It is highly preferred that R2Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, normal-butyl etc..
Most preferably, R2Selected from methyl or ethyl.
Further, the alkali of step (1) is selected from diisopropylethylamine (DIPEA), 1,8- diazabicyclos [5.4.0] 11
Carbon -7- alkene (DBU), 4-dimethylaminopyridine (DMAP), pyridine etc. it is one or more；Preferably, it is selected from diisopropylethylamine
(DIPEA)。
Further, the organic solvent of step (1) is selected from acetonitrile, dichloromethane, methanol, tetrahydrofuran, Isosorbide-5-Nitrae-dioxy six
It is one or more in ring, DMF, dimethyl sulfoxide；Preferably, it is selected from acetonitrile.
Further, the reaction temperature of step (1) is 20-80 DEG C；Preferably, reaction temperature is 40-65 DEG C.
Further, the reaction time of step (1) is 0.5-5 hours；Preferably, the reaction time is 1-3 hours.
Further, the molar ratio of formula (IV) compound and formula (III) compound is 1：(1-5)；Preferably, formula
(IV) molar ratio of compound and formula (III) compound is 1：1.5.
Further, the molar ratio of formula (IV) compound and alkali is 1：(1-10)；Preferably, formula (IV) compound with
The molar ratio of alkali is 1：3.
Further, when R is tertbutyloxycarbonyl, the preparation method of compound I is：Formula (IV) compound is dissolved in acetonitrile
In, it is then added DIPEA, under nitrogen protection, is warming up to 40-65 DEG C.Methyl bromoacetate, insulated and stirred 1.5h is then added.It is cold
But it to room temperature, is poured into water, organic solvent extracts liquid separation, and organic phase is dry, is concentrated to give formula (II) crude compound.By the crude product
It is dissolved in methanol, lye is then added, Hydrolysis At Room Temperature is complete.Concentration removes methanol, is poured into water, and organic solvent extracts liquid separation,
Water phase adjusts pH value with acid solution, has a large amount of solids to be precipitated, and filtering, filter cake collects to obtain formula (I) compound.
In addition, the present invention also provides the preparation method of formula (IV) compound, include the following steps：
(a) formula (VI) compound and amino protecting agent in the presence of alkali, react production (V) and change in organic solvent
Close object；
(b) formula (V) compound and N,N-dimethylformamide dimethylacetal (DMF-DMA) or and secondary aliphatic amine
Add orthoformate or reaction production (IV) compound；
Reaction route is as follows：
Wherein, R is amino protecting group, the amino protecting group be selected from tertbutyloxycarbonyl, acetyl group, tablet held before the breast by officials methoxycarbonyl group,
Benzyloxycarbonyl group, allyloxycarbonyl or trimethylsilyl ethoxycarbonyl etc.；Preferably, R is tertbutyloxycarbonyl.
Further, the alkali in step (a) be selected from potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, lithium diisopropylamine,
Lithium hexamethyldisilazide, sodium hexamethyldisilazide, 11 carbon -7- alkene of 1,8- diazabicyclos [5.4.0]
((DBU)), 4- dimethylamino naphthyridines, pyridine, imidazoles, it is one or more in sodium hydride etc.；Preferably, it is selected from diisopropyl
Lithium amide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, sodium hydride；Most preferably, it is selected from sodium hydride.
Further, the organic solvent used in step (a) is aprotic solvent, selected from tetrahydrofuran, DMF, toluene, two
It is one or more in first sulfoxide, 1,4- dioxane；Preferentially, solvent for use be selected from tetrahydrofuran, Isosorbide-5-Nitrae-dioxane,
It is one or more in DMF, toluene, dimethyl sulfoxide etc.；Most preferably, it is selected from toluene.
Further, the molar ratio of step (a) Chinese style (VI) compound and amino protecting agent is 1：(1~5)；It is preferred that
The molar ratio of ground, formula (VI) compound and amino protecting agent is 1：(1.5~3).
Further, the molar ratio of step (a) Chinese style (VI) compound and alkali is 1：(0.1~5)；Preferably, it closes
The molar ratio of object VI and alkali is 1：(1.5~3).
Further, in step (b), orthoformate is original acid A ester or ethyl orthoformate.
Further, in step (b), the molar ratio of formula (V) compound and secondary aliphatic amine, orthoformate is 1：
(1.5~5)：(1.5~5)；Preferably, molar ratio is：1：2：2.
Further, in step (b), the molar ratio of formula (V) compound and DMF-DMA are 1：(2~5), preferably
Ground is 1：3.
Further, the reaction condition of step (b) is：When selected amine is dialkylamine, pyrrolidines, piperidines, morpholine,
Reaction carries out in triethyl orthoformate or trimethyl orthoformate；When using DMF-DMA as amination reagent, reaction dissolvent
For methanol, ethyl alcohol, acetonitrile or solvent-free reaction.
When R is tertbutyloxycarbonyl, the preparation method of formula (IV) compound is：Formula (VI) compound is dissolved in aprotic solvent
In, alkali is added, after reacting at room temperature 0.5~1 hour, Boc acid anhydrides is added, is warming up to 50 DEG C to the reaction was complete, pours into ice water and quench
It goes out, extracts liquid separation, merge organic phase, dilute hydrochloric acid solution washing, organic phase drying is concentrated to give formula (V) crude compound, is not required to
It is refined, directly carry out next step reaction.Formula (V) compound is dissolved in DMF-DMA, it is complete to be heated to back flow reaction, is cooled to
It is poured into ice water after room temperature, extracts liquid separation, merge organic phase, organic phase drying, concentration.Normal heptane is added into concentrate, has
A large amount of solids are precipitated, and filtering obtains formula (IV) compound.
Beneficial effects of the present invention：
1) one pot reaction method is used by the process of formula (IV) compound of formula (II) compound, intermediate in reaction process
Ring-closure reaction can be directly carried out under the action ofs the larger alkali of steric hindrance such as diisopropylethylamine etc., reduced by-product and generated, target
Product purity is high, is easy to purify, yield significantly improves.
2) starting material is cheap and easy to get, and reaction route step is few, and reaction condition is mild, avoids poisonous reagent, deep-etching
The use of property reagent, the three wastes are few, are suitable for industrialized large-scaled production.
Specific implementation mode
Further illustrated the present invention below by embodiment, for a person skilled in the art, should not will under
Row embodiment is interpreted as limitation of the present invention, instructs according to prior art, is modified or improved to it and belongs to the present invention's
In protection domain.
Embodiment 1：The preparation of formula (IV a) compound
Modus ponens (VI) compound (65g, 0.73mol) is dissolved in 1000mL toluene, be added portionwise 60% sodium hydride (38g,
0.95mol), after 30min being stirred at room temperature, DMAP (8.9g, 0.073mol) is added, be then added dropwise Boc acid anhydrides (167g,
0.766mol), drop finishes, and is warming up to 50 DEG C of reaction about 2h, pours into 1600mL ice water, extract liquid separation, water phase normal heptane 200mL
Extraction merges organic phase, is washed with 500mL dilute hydrochloric acid solutions (1mol/L), and organic phase is dried with anhydrous anhydrous magnesium sulfate, decompression
Concentration.1000mL normal heptanes, filtering are added into concentrate, filtrate is concentrated to give 144g brown oils formula (V a) compound, is not required to
Purifying directly carries out next step reaction.
144g formulas (V a) compound obtained by previous step is added in DMF-DMA (263g, 2.21mol), is heated to back
Stream reacts about 3h, after the reaction of formula (V a) compound substantially completely afterwards reaction system is cooled to room temperature, pour into 1200mL ice water
In, liquid separation is extracted with ethyl acetate (150mL × 3), merges organic phase and is dried with anhydrous magnesium sulfate, is concentrated under reduced pressure.To concentration
200mL normal heptanes are added in liquid, there are a large amount of solids to be precipitated, stir 30min, filtering, filter cake is washed with 50mL normal heptanes, collects filter
Cake dries to obtain yellow solid 118g.Two step yields：66.2%.
1H-NMR (400MHz, CDCl3)：δ 1.52 (9H, s), 2.92 (3H, brs), 3.19 (3H, brs), 3.60 (3H,
S), 6.45 (1H, d, J=12.0Hz), 8.26 (1H, d, J=12.0Hz).
Embodiment 2:The preparation of formula (Ia) compound
Formula (IV a) compound (15g, 0.06mol) is added in 150mL acetonitriles, then be added DIPEA (24g,
0.186mol), under nitrogen protection, 50 DEG C are warming up to.14.1g methyl bromoacetates are added dropwise, drips and finishes insulated and stirred 1.5h.Wait for formula (IV
A) system is cooled to room temperature after compound fundamental reaction is complete, is poured into 1500mL water, is extracted with ethyl acetate (100mL × 3)
Liquid separation is taken, organic phase is merged, filtrate is concentrated to give sepia solid type (II a) after filtering and changed by the drying of organic phase anhydrous magnesium sulfate
Object 15.5g is closed, is not required to purify, is directly used in and reacts in next step.
A small amount of reaction solution is taken, silicagel column is crossed and carries out nuclear-magnetism structural identification after purification.1H-NMR (400MHz, DMSO-d6)：δ
1.57 (9H, s), 3.39 (3H, s), 3.84 (3H, s), 6.46 (1H, d, J=4.0Hz), 7.61 (1H, d, J=4.0Hz).
Formula (II a) compound (15.5g) obtained by previous step is added in 200mL methanol, 96mL 1mol/L are then added
Sodium hydroxide solution stirs 16h at 30 DEG C.Stop reaction after the reaction was complete after formula (II a) compound, vacuum distillation removes first
Alcohol will be added 500mL water and 100mL dichloromethane, extract liquid separation in concentrate, collect water phase and use dilute hydrochloric acid solution
(1mol/L) adjusts pH value to 4.5 or so, has a large amount of solids to be precipitated, stirs 5min.Filtering, pale yellow solid is dried to obtain by filter cake
11.4g.Yield：73.9%.1H-NMR (400MHz, DMSO-d6)：δ 1.52 (9H, s), 3.35 (3H, s), 6.65 (1H, d, J=
4.4Hz), 7.52 (1H, d, J=4.4Hz), 12.65 (1H, brs).
Embodiment 3:The preparation of formula (IV b) compound
Formula (VI) compound (65g, 0.73mol) is dissolved in 1000mL tetrahydrofurans, be added portionwise potassium carbonate (200g,
1.45mol), after 30min being stirred at room temperature, DMAP (8.9g, 0.073mol) is added, aceticanhydride (112g, 1.1mol), drop is then added dropwise
Finish and be warming up to 50 DEG C of reaction about 2h, pour into 1600mL ice water, extract liquid separation, water phase is extracted with normal heptane 200mL, is merged organic
Phase is washed with 500mL dilute hydrochloric acid solutions (1mol/L), the drying of organic phase anhydrous magnesium sulfate, concentration.It is added into concentrate
1000mL normal heptanes, filtering, filtrate are concentrated to give 131g brown oils formula (V b) compound.
By formula (V b) compound (131g), trimethyl orthoformate (159g, 1.5mol), diisopropylamine (151.5g,
It 1.5mol) is added sequentially in reaction vessel, is heated to back flow reaction about 3h, it, will after after formula (V b) compound, the reaction was complete
System is cooled to room temperature, and is poured into 1200mL ice water, and liquid separation is extracted with ethyl acetate (150mL × 3), is merged organic phase and is used nothing
Water magnesium sulfate is dried, concentration.200mL normal heptanes are added into concentrate, there are a large amount of solids to be precipitated, stir 30min, filter, filter
Cake is washed with 50mL normal heptanes, is collected filter cake and is dried to obtain yellow solid 97g.Two step yields：55%.
Embodiment 4:The preparation of formula (I b) compound
Formula (IV b) compound (14.5g, 0.06mol) is added in 150mL tetrahydrofurans, then be added DBU (9.1g,
0.06mol), under nitrogen protection, ethyl chloroacetate (32.6g, 0.3mol) is added dropwise under the conditions of 20~30 DEG C, drips and finishes insulated and stirred
5h.Stop reaction after the amount of formula (IV b) compound is no longer further reduced, pours into 1500mL water, use ethyl acetate
(100mL × 3) extract liquid separation, merge organic phase, and filtrate is concentrated to give sepia after filtering and consolidated by the drying of organic phase anhydrous magnesium sulfate
Body formula (II b) compound 12.5g, is not required to purify, and is directly used in and reacts in next step.
Previous step 12.5g formulas (II b) crude compound, is dissolved in 100mL methanol, and a concentration of 1mol/ of 100mL are then added
The sodium hydroxide solution of L, 30 DEG C of stirring 12h.Concentration removes methanol, pours into 400mL water, dichloromethane (100mL) extraction point
Liquid, water phase 1mol/L hydrochloric acid solutions adjust pH value to 4.5 or so, have a large amount of solids to be precipitated, stir 5min.Filtering, filter cake are received
Collection dries to obtain pale yellow solid 8.5g.Two step yields：71.2%.
Embodiment 5:The preparation of formula (IV c) compound
Formula (V a) compound (15.1g, 0.08mol), morpholine (17.4g, 0.2mol) are dissolved in triethyl orthoformate
In (29.6g, 0.2mol), it is heated to back flow reaction about 5h, system is cooled to room after the reaction was complete after formula (V a) compound
Temperature is poured into 1200mL ice water, is extracted liquid separation with ethyl acetate (150mL × 3), is merged organic phase, organic phase anhydrous slufuric acid
Magnesium is dried, concentration.200mL normal heptanes are added into concentrate, there are a large amount of solids to be precipitated, stir 30min, filtering, filter cake is used
50mL normal heptanes wash, and collect filter cake and dry to obtain yellow solid 6.8g.Yield：29.7%.
Embodiment 6:The preparation of formula (I a) compound
Formula (IV c) compound (14.3g, 0.05mol) is dissolved in 200ml DMF, then be added pyridine (40g,
0.5mol), under nitrogen protection, 80 DEG C are warming up to.Benzyl acetate bromide (11.5g, 0.05mol) is then added dropwise, drips and finishes insulated and stirred
0.5h.Reaction system is cooled to room temperature after the amount of formula (IV c) compound is no longer reduced, is poured into 500mL water, with acetic acid second
Ester (200mL × 3) extracts liquid separation, merges organic phase, and organic phase is dried with anhydrous magnesium sulfate, is concentrated to give sepia solid type (II
C) compound 17g is not required to purify, and is directly used in next step.
17g formulas (II c) compound is dissolved in 200mL methanol, then addition 80mL 1mol/L sodium hydroxide solutions, 30
DEG C stirring 10h.Concentration removes methanol, pours into 100mL water, and 30mL dichloromethane is added and extracts liquid separation, water phase 1mol/L salt
Acid solution adjusts pH value to 4.5 or so, has a large amount of solids to be precipitated, stirs 5min.Pale yellow solid is dried to obtain in filtering, filter cake collection
7.9g.Two step yields：61.5%.
Comparative example
Bibliography, using triethylamine as alkali, Multistep feeding：
15g formulas (IV a) compound is dissolved in 150mL acetonitriles, 14.1g methyl bromoacetates are added dropwise, drop, which finishes, to be stirred at room temperature
19g triethylamines are then added in 1.5h, are warming up to 50 DEG C of reaction 1.5h.20 DEG C are cooled to, is poured into 1500mL water, ethyl acetate
(100mL × 3) extract liquid separation, merge organic phase, and organic phase is dried with anhydrous magnesium sulfate, is concentrated to give dark brown solid 13g, is not required to
Purifying is directly used in next step.
13g formulas (II a) crude compound is dissolved in 200mL methanol obtained by previous step, and 96mL1mol/L hydrogen-oxygens are then added
Change sodium solution, 30 DEG C of stirring 16h.Concentration removes methanol, pours into 500mL water, and dichloromethane (100mL) extracts liquid separation, water phase
PH value is adjusted to 4.5 or so with 1mol/L hydrochloric acid solutions, is had a small amount of solid to be precipitated, is stirred 5min.Filtering, filter cake collection are dried
Pale yellow solid 2.8g.Two step yields：18%.
Using tetrahydrofuran as solvent, other conditions are constant, and formula (I) compound yield is 16%.
Using dichloromethane as solvent, other conditions are constant, and formula (I) compound yield is 13%.
The triethylamine in aforesaid operations is replaced with sodium methoxide, the solvent acetonitrile in aforesaid operations, Qi Tacao are replaced with methanol
Make it is constant, formula (I) compound yield be 10%.
Claims (9)
1. a kind of preparation method of Raltitrexed intermediate formula (I) compound：
It is characterized in that, mainly including the following steps that：
(1) formula (IV) compound and formula (III) compound carry out coupling and ring-closure reaction obtain in organic solvent in the presence of a base
To formula (II) compound；
(2) ester hydrolysis reaction production (I) compound occurs for formula (II) compound.
Wherein, R is amino protecting group, and the amino protecting group is selected from tertbutyloxycarbonyl, acetyl group, tablet held before the breast by officials methoxycarbonyl group, benzyloxy
Carbonyl, allyloxycarbonyl or trimethylsilyl ethoxycarbonyl；
R1For-NR3R4, pyrrolidinyl, piperidyl or morpholinyl, the R3And R4It is separately alkyl.
X is halogen, selected from chlorine, bromine, iodine；
R2Selected from alkyl or benzyl；
Alkali described in step (1) is selected from diisopropylethylamine, 11 carbon -7- alkene of 1,8- diazabicyclos [5.4.0], 4- diformazan ammonia
It is one or more in yl pyridines or pyridine.
2. preparation method according to claim 1, which is characterized in that alkali described in step (1) is diisopropylethylamine.
3. preparation method according to claim 1, which is characterized in that R is tertbutyloxycarbonyl, and X is bromine, R2Selected from methyl, second
Base, propyl, isopropyl, butyl, isobutyl group, normal-butyl.
4. preparation method according to claim 1, which is characterized in that step (1) described organic solvent is selected from acetonitrile, dichloro
It is one or more in methane, methanol, tetrahydrofuran, 1,4- dioxane, DMF, dimethyl sulfoxide.
5. preparation method according to claim 1, which is characterized in that reaction temperature is 20-80 DEG C in step (1), reaction
Time is 0.5-5 hours.
6. preparation method according to claim 1, which is characterized in that formula (IV) compound feeds intake with formula (III) compound
Molar ratio is 1：(1~5)；The molar ratio of formula (IV) compound and alkali is 1：(1~10).
7. preparation method according to claim 1, which is characterized in that the preparation method of formula (IV) compound includes following step
Suddenly：
(a) formula (VI) compound and amino protecting agent in the presence of alkali, react production (V) compound in organic solvent；
(b) compound V adds orthoformate to react production (IV) compound with DMF-DMA or with secondary aliphatic amine；
Wherein, R is as described in claim 1.
8. preparation method according to claim 7, which is characterized in that alkali described in step (a) is selected from potassium carbonate, carbonic acid
Caesium, sodium methoxide, sodium ethoxide, lithium diisopropylamine, lithium hexamethyldisilazide, sodium hexamethyldisilazide, 1,8- bis-
One or more of 11 carbon -7- alkene of azabicyclic, 4-dimethylaminopyridine, pyridine, imidazoles, sodium hydride；It is described organic molten
Agent is aprotic solvent, one or more in tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, DMF, toluene, dimethyl sulfoxide.
9. preparation method according to claim 7, which is characterized in that orthoformate described in step (b) is orthoformic acid first
Ester or ethyl orthoformate.
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| CN102127063A (en) * | 2011-01-06 | 2011-07-20 | 深圳市普迈达科技有限公司 | New synthesis technology of anti-cancer drug Raltitrexed |
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| CORNELIA HEYDE，等: "A Simple Route to N,N-Dialkyl Derivatives of 2-Amino-5-thiophenecarboxylates", 《EUR. J. ORG. CHEM.》 * |
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