CN110016024A - A kind of key intermediate and its preparation method and application synthesizing CDK4/6 double inhibitor - Google Patents
A kind of key intermediate and its preparation method and application synthesizing CDK4/6 double inhibitor Download PDFInfo
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- CN110016024A CN110016024A CN201810018397.5A CN201810018397A CN110016024A CN 110016024 A CN110016024 A CN 110016024A CN 201810018397 A CN201810018397 A CN 201810018397A CN 110016024 A CN110016024 A CN 110016024A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a kind of chloro- 7- cyclopenta-N of synthesis 2-; N- dimethyl -7H- pyrrolo- [2; 3-d] pyrimidine -6- carboxamide intermediate (compound I) and its preparation method and application; the following steps are included: with 2; the chloro- 7H- pyrrolo- [2 of 4- bis-; 3-d] pyrimidine (compound II) be starting material, first pass through protecting group and carry out prepare compound III；Compound III reacts to obtain compound IV by inserting carbonyl；Compound V is obtained using Deprotection；Selective dechlorination obtains compound VI；Cyclopenta obtains compound I on compound VI；Compound I hydrolyzes to obtain compound VII；Chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide (compound VIII) of 2- is made in amidation again.
Description
Technical field
The present invention relates to pharmaceutical intermediates to synthesize field, relates in particular among a kind of CDK4/6 double inhibition agent key
The preparation method and application of chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of body 2-.
Background technique
Chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2- is the one of medicine synthesis
Kind important intermediate.It can be used to prepare a kind of cell cycle protein dependent kinase (CDK4/6 double inhibitor), Ke Yixian
Write and inhibit the growth of a variety of nerve-cell tumors, be used for breast cancer treatment of late stage, Short Term Clinical result of study show it is significant in efficacy, therefore
It has a vast market foreground.
Novartis Co., Ltd discloses chloro- 7- cyclopenta-N, the N- dimethyl -7H- pyrrolo- of 2- in patent CN102186856 (B)
The synthetic method of [2,3-d] pyrimidine -6- formamide:
Reagent and condition: (a) cyclopenta amine, DIPEA, room temperature, overnight, yield: 89%；(b) acraldehyde diethyl second contracts
Aldehyde, Pd (PPh3)2Cl2, CuI, TEA, DMF, 100 DEG C, 13h, 43%；(c) TBAF, 65 DEG C, 2h, 82%；(d) dioxanes is dense
HCl, room temperature, 82%；(e) potassium hydrogen persulfate, DMF, room temperature, 6h, 85%；(f) diisopropyl ethyl amine, HBTU, dimethyl methyl
Amide, dimethyl amine/ethanol solution, room temperature, 30min, 79%.
The route has the following problems: selecting cost of material costly, has used more noble metal catalyst；By
The deficiencies of 6 steps reaction, coupling reaction yield is relatively low；Total recovery is 17.28%, and yield is low, high process cost, pollution weight.
Novartis Co., Ltd discloses chloro- 7- cyclopenta-N, the N- dimethyl -7H- pyrrolo- of 2- in patent CN105399743A
Another preparation method of [2,3-d] pyrimidine -6- formamide:
Reagent and condition: (g) cyclopenta amine, DIPEA, 40 DEG C, overnight, yield 88%；(h) propargyl alcohol, Pd (PPh3)2Cl2, TBAF, THF/H2O, reflux, 2h, yield 47.4%；(i) TBAF, THF, 60 DEG C, 1h；(j)MnO2, NaCN, dimethylamine/
THF, DMF.
The route has the following problems: select propilolic alcohol be coupled as side chain, reaction system impurity is more, yield compared with
It is low；The impurity that compound XIV ring closure reaction generates is difficult to remove；During compound XV prepares VIII, severe toxicity has been used
Cymag, not environmentally；And use a large amount of manganese dioxide as oxidant；Technique is enlarged inconvenient.
Shanghai Institute of Pharmaceutical Industry discloses chloro- 7- cyclopenta-N, the N- dimethyl-of 2- in patent CN107266451A
Another preparation method of 7H- pyrrolo- [2,3-d] pyrimidine -6- formamide:
Reagent and condition: (k) Pd (PPh3)2Cl2, TBAF, THF, reflux, for 24 hours, yield: 88.2%；(l) TBAF, THF,
90 DEG C, 12h, yield 84%；(m) concentrated hydrochloric acid, EA, room temperature, 8h, yield 98%；(n) NaBr, tetramethyl piperidine, THF, NaClO,
0 DEG C-room temperature, 12h, yield: 86%；(o)I2, the hydrogen peroxide tert-butyl alcohol, DMF, 70 DEG C, for 24 hours, yield 72.8%.
Although the route increases on yield than above-mentioned two route, problem remain, however, that using
Expensive metallic catalyst；Raw material compound XVI is difficult to obtain；Peroxide is used in final step, and there are certain safety winds
Danger.Therefore it is not suitable for industrialized production.
Summary of the invention
Goal of the invention: the purpose of the present invention is overcoming above-mentioned the shortcomings of the prior art, the synthesis chloro- 7- ring penta of 2- is provided
The new intermediate and its preparation method and application of base-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide, should
Method is easy to operate, high income, is suitable for large scale preparation.
The present invention provides a kind of compounds of structure formula (I):
The preparation method of compound I, comprising:
Wherein: R1For benzenesulfonyl or p-toluenesulfonyl.
In the step of compound II prepare compound III, acyl chlorides is benzene sulfonyl chloride or paratoluensulfonyl chloride；The alkali
For in sodium hydride, 11-7- alkene of 1,8- diazabicyclo [5.4.0], triethylamine, diisopropyl ethyl amine or above-mentioned alkali again
The N of catalytic amount, N-4- dimethylamino naphthyridine is added；Reaction dissolvent is methylene chloride, tetrahydrofuran or Isosorbide-5-Nitrae-dioxane；Instead
Answering temperature range is 0~30 DEG C.
In the step of compound III prepare compound IV, the alkali is diisobutylamino lithium, two (trimethyl silicon substrates)
Lithium amide or two (trimethyl silicon substrate) Sodamides；Carbon dioxide is carbon dioxide gas or dry ice.Range of reaction temperature be-
100~0 DEG C；The molar ratio of compound III and alkali is 1: 1~1: 10.
In the step of compound IV prepare compound V, alkali is sodium methoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide, tertiary fourth
Sodium alkoxide or potassium tert-butoxide；0~40 DEG C of range of reaction temperature；The molar ratio of compound IV and alkali is 1: 1~1: 3.
In the step of compound V prepare compound VI, acidic materials are ammonium chloride or acetic acid.Range of reaction temperature 50~
100℃；The molar ratio of compound V and Zn are 1: 5~1: 10.
In the step of compound VI prepare compound I, the alkali selects triethylamine, DIPEA or cesium carbonate；Reaction temperature
50~100 DEG C of range of degree；The molar ratio range of compound VI, alkali and bromocyclopentane are 1: 2~5: 2~5；Reaction dissolvent is
DMF, DMA or 1,4- dioxane.
Compound I occurs hydrolysis in alkaline condition and obtains prepare compound VII:
Compound VII occurs amidation process with dimethylamine and obtains compound VIII under condensing agent effect:
In above-mentioned two reaction equation, the step of compound I prepare compound VII in, the alkali selects sodium hydroxide, hydrogen
Potassium oxide or lithium hydroxide；20~100 DEG C of range of reaction temperature.
In the step of compound VII prepare compound VIII, alkali selects DIPEA, DBU or TEA；Condensing agent selection CDI,
EDCI, HATU or HBTU；The reagent of dimethylamine selects dimethylamine methanol solution, dimethylamine tetrahydrofuran solution, diformazan
Amine hydrochlorate；Range of reaction temperature -20~50 DEG C.
With chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine (compound II) of 2,4- bis- for starting material, protecting group is first passed through
Prepare compound III；Compound III reacts to obtain compound IV by inserting carbonyl；Compound V is obtained using Deprotection；Choosing
The dechlorination of selecting property obtains compound VI；Cyclopenta obtains compound I on compound VI；Compound I hydrolyzes to obtain compound VII；Again
Chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide (compound VIII) of 2- is made in amidation.
Beneficial effect
The present invention for raw material, first carrys out prepare compound III to protecting group on N with (compound II)；Carbonyl is inserted again to react to obtain
Compound IV；Deprotection obtains compound V；Selective dechlorination prepare compound VI；Upper cyclopenta obtains new intermediate again
Compound I；Compound I hydrolysis；Last amidation obtains compound VIII.It is anti-that the preparation general line of compound VIII amounts to 7 steps
It answers, for total recovery up to 29.5%, product purity is up to 99% or more.Route steps of the present invention are short, and mild condition is easy to operate,
Process stabilizing, purifying is convenient, is easy to amplify production, and more outstanding is to effectively prevent used severe toxicity in the prior art
Chemicals Cymag makes entire synthesis technology safety, environmental protection.
The abbreviation for the reaction reagent being related in specification is as follows:
11-7- alkene of DBU:1,8- diazabicyclo [5.4.0]；
DIPEA: diisopropyl ethyl amine；
TEA: triethylamine；
DMAP:N, N-4- dimethylamino naphthyridine；
LDA: diisobutylamino lithium；
LiHMDS: two (trimethyl silicon substrate) lithium amides；
NaHMDS: two (trimethyl silicon substrate) Sodamides；
DCM: methylene chloride；
THF: tetrahydrofuran；
2-MeTHF:2- methyltetrahydrofuran；
DMF:N, dinethylformamide；
DMA:N, N- dimethyl acetamide；
EA: ethyl acetate；
CDI: carbonyl dimidazoles；
EDCI:1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride；
HATU: hexafluorophosphoric acid O- (7- azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylurea；
HBTU:O- benzotriazole-tetramethylurea hexafluorophosphate；
HOBt:1- hydroxybenzotriazole；
TBAF: tetrabutyl ammonium fluoride.
Specific embodiment
Combined with specific embodiments below, the present invention is furture elucidated, and the present embodiment is based on the technical solution of the present invention
Under implemented, it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Embodiment 1
The preparation of compound III-1:
In 50L bilayer kettle, compound II (2500g, 13.3mol, 1.0e.q.) is added in 20L methylene chloride, is added three
Ethamine (2019g, 19.95mol, 1.5e.q.), finishes, and at 0 DEG C, is added dropwise benzene sulfonyl chloride (2584g, 14.63mol, 1.1e.q.),
It 0~10 DEG C of temperature control, is added dropwise, 10 DEG C are stirred to react 5h, and LC-MS detects end of reaction.The water of 25L is added into reaction solution,
Rear liquid separation is sufficiently stirred, organic phase is washed with 25L saturated sodium bicarbonate solution, liquid separation after 25L water washing, and anhydrous magnesium sulfate is added
It dries, filters, after evaporating solvent under reduced pressure, is beaten with petroleum ether, dry, obtaining compound III-1 is faint yellow solid 3675.0g,
Yield 84.2%.1HNMR (400MHz, CDCl3, δ ppm) and 8.26-8.25 (d, 2H), (7.78-7.58, m, 4H), 6.72-6.71
(d, 1H).
The preparation of compound IV-1:
Diisopropylamine (616.7g, 6.09mol, 1.0e.q.) and 20L tetrahydrofuran are added in 50L bilayer kettle, -40 DEG C
It is added dropwise n-BuLi (2436mL, 6.09mol, 1.0e.q.), stirs 30min at 0 DEG C, the LDA produced is stand-by.Cool to -100
DEG C, the 10L tetrahydrofuran solution of compound III-1 (2000g, 6.09mol, 1.0e.q.) is added dropwise, is stirred to react at -100 DEG C
About 1kg dry ice is added in 1h, and 30min is stirred to react after adding, and LC-MS shows end of reaction.It is slowly added dropwise 3L's in toward reaction solution
Saturated aqueous ammonium chloride quenching reaction.Dilute hydrochloric acid adjusts pH to 2, EA and extracts, and after water washing, liquid separation subtracts after organic phase is dry
Solvent is evaporated off in pressure, dry that compound IV-1 is yellow solid 2000g, yield 88.2%, purity after petroleum ether mashing is added
98%.1HNMR (400MHz, DMSO-d6, δ ppm), 8.28-8.25 (d, 2H), 7.85-7.75 (m, 3H), 7.40 (s, 1H).
The preparation of compound V:
By compound IV-1 (2000g, 5.3mol, 1.0e.q.), 4L tetrahydrofuran and 8L water are added to 50L single layer kettle
In, it finishes, at 0 DEG C, the aqueous solution 4L of NaOH (212g, 5.3mol, 1.0e.q.) is added dropwise, is added dropwise, is stirred to react at 0 DEG C
1h, LC-MS show end of reaction.Reaction solution is added in dilute hydrochloric acid, is precipitated a large amount of off-white powders, dry chemical combination after suction filtration
Object V is faint yellow solid 1246g, direct plunges into and reacts in next step.1HNMR (400MHz, DMSO-d6, δ ppm) and 13.50 (s, 1H),
7.21 (s, 1H).
The preparation of compound VI:
Compound V (1246g, 5.3mol, 1.0e.q.) is added in the reaction kettle of 50L, the methanol of 6L, 3.5L is added
DMF, ammonium chloride (1219g, 22.79mol, 4.3e.q.), under water-bath, be added portionwise zinc powder (3465.5g, 53.1mol,
10e.q.), it finishes, after being stirred to react for 24 hours at 50 DEG C, LC-MS shows end of reaction.It filters, residue is first eluted with methanol, then is used
Eluent methylene chloride, evaporating solvent under reduced pressure, raffinate are precipitated down to a large amount of yellow solids in the dilute hydrochloric acid of ice, are precipitated, are sufficiently stirred
Afterwards, it is dry that compound VI is yellow solid 794.8g, two step yields 75.9% after ethyl alcohol, petroleum ether are beaten respectively.1HNMR
(400MHz, DMSO-d6, δ ppm), 13.05 (s, 1H), 9.08 (s, 1H), 7.21 (s, 1H).The preparation of compound I:
In the single layer kettle of 50L, compound VI (794g, 4.1mol, 1.0e.q.) is added in the DMF of 7L, carbon is added
Sour caesium (2672g, 8.2mol, 2.0e.q.), etamon chloride (154.6g, 0.93mol, 0.2e.q.), fast drop bromo
Pentamethylene (1222g, 8.2mol, 2.0e.q.), is heated to 100 DEG C, is stirred to react 6h.LC-MS shows end of reaction.It will reaction
Liquid is cooled to 40 DEG C, and the tertiary ether of first is added, filters after stirring, and filtrate is down in ice water, the tertiary ether extraction of first, merges organic phase, washing,
Methanol mashing is added in evaporating solvent under reduced pressure, and the compound I after drying is yellow solid 958.1g, yield 70%.1HNMR
(400MHz, CDCl3, δ ppm) and 9.09 (s, 1H), 5.67-5.63 (t, 1H), 5.38-5.35 (m, 2H), 2.51-2.26 (m,
2H), 2.04-1.92 (m, 6H), 1.82-1.74 (m, 8H).(ESI-TOF) m/z:[M+2]+calcd for C17H20ClN3O2:
333.82；Found:333；335.
Embodiment 2
The preparation of compound III-2:
In 50L bilayer kettle, compound II (2500g, 13.3mol, 1.0e.q.) is added in 30L THF, at 0 DEG C, in batches
It is added NaH (797.8g, 19.95mol, 1.5e.q.), finishes, at 0 DEG C, dropwise addition paratoluensulfonyl chloride (3042g, 15.96mol,
1.2e.q.), 0~10 DEG C of temperature control, is added dropwise, and 20 DEG C are stirred to react 6h, and LC-MS detects end of reaction.It is added into reaction solution
Rear liquid separation is sufficiently stirred in the water of 35L, and organic phase is washed with 30L saturated sodium bicarbonate solution, liquid separation after 30L water washing, and nothing is added
Water magnesium sulfate dries, filters, and after evaporating solvent under reduced pressure, is beaten with petroleum ether, dry, and obtaining compound III-2 is faint yellow solid
3881.3g, yield 85.3%.
The preparation of compound IV-2:
The 10L tetrahydrofuran solution of compound III-2 (2000g, 5.84mol, 1.0e.q.) is cooled to -50 DEG C, is added dropwise
The THF solution of 2.5M NaHMDS (11.69L, 29.22mol, 5.0e.q.), is added dropwise, and 1h is stirred to react at -50 DEG C, is added
About 1kg dry ice, is stirred to react 30min after adding, LC-MS shows end of reaction.Saturated ammonium chloride is slowly added dropwise in toward reaction solution
Aqueous solution quenching reaction.Dilute hydrochloric acid adjusts pH to 2, EA and extracts, and after water washing, liquid separation removes under reduced pressure molten after organic phase is dry
Agent, it is dry that compound IV-2 is yellow solid 1921.7g, yield 85.2%, purity 98% after petroleum ether mashing is added.
The preparation of compound V:
By compound IV-2 (1921g, 4.98mol, 1.0e.q.), 10L methanol is added in 50L single layer kettle, finishes, 0
At DEG C, the methanol solution 4L of sodium methoxide (537.4g, 9.95mol, 2.0e.q.) is added dropwise, is added dropwise, is stirred to react at 20 DEG C
3h, LC-MS show end of reaction.Reaction solution is added in dilute hydrochloric acid, is precipitated a large amount of off-white powders, dry chemical combination after suction filtration
Object V is faint yellow solid 1156g, direct plunges into and reacts in next step.1HNMR (400MHz, DMSO-d6, δ ppm) and 13.5 (s, 1H),
7.21 (s, 1H).
The preparation of compound VI:
Compound V (1156g, 4.98mol, 1.0e.q.) is added in the reaction kettle of 50L, the ethyl alcohol of 9L, acetic acid is added
(1794g, 29.88mol, 6.0e.q.) under water-bath, is added portionwise zinc powder (2428.5g, 37.35mol, 7.5e.q.), finishes,
After being stirred to react for 24 hours at 100 DEG C, LC-MS shows end of reaction.It filters, residue is first eluted with methanol, then is drenched with methylene chloride
It washes, evaporating solvent under reduced pressure, raffinate is precipitated down to a large amount of yellow solids in the dilute hydrochloric acid of ice, are precipitated, after being sufficiently stirred, ethyl alcohol, stone
It is dry that compound VI is yellow solid 768.5g, two step yields 78.1% after oily ether is beaten respectively.1HNMR (400MHz,
DMSO-d6, δ ppm), 13.05 (s, 1H), 9.08 (s, 1H), 7.21 (s, 1H).
The preparation of compound I:
In the single layer kettle of 50L, compound VI (768.5g, 3.89mol, 1.0e.q.) is added to Isosorbide-5-Nitrae-dioxy of 7L
In six rings, it is added TEA (1379g, 13.61mol, 3.5e.q.), dropwise addition bromocyclopentane (2029g, 13.61mol,
3.5e.q.), 50 DEG C are heated to, 6h is stirred to react.LC-MS shows end of reaction.Reaction solution is cooled to 30 DEG C, first uncle is added
Ether filters after stirring, and for filtrate down in ice water, the tertiary ether extraction of first merges organic phase, washing, methanol is added in evaporating solvent under reduced pressure
Mashing, the compound I after drying are yellow solid 950.5g, yield 73.2%.1HNMR (400MHz, CDCl3, δ ppm) and 9.09
(s, 1H), 5.67-5.63 (t, 1H), 5.38-5.35 (m, 2H), 2.51-2.26 (m, 2H), 2.04-1.92 (m, 6H), 1.82-
1.74 (m, 8H).(ESI-TOF) m/z:[M+2]+calcd for C17H20ClN3O2: 333.82；Found:333；335.
Embodiment 3
The preparation of compound III-1:
In 50L bilayer kettle, compound II (2500g, 13.3mol, 1.0e.q.) is added in 20L methylene chloride, is added
DBU (3035g, 19.95mol, 1.5e.q.), finishes, and at 0 DEG C, is added dropwise benzene sulfonyl chloride (2819g, 15.96mol, 1.2e.q.),
It 0~10 DEG C of temperature control, is added dropwise, 30 DEG C are stirred to react 5h, and LC-MS detects end of reaction.The water of 25L is added into reaction solution,
Rear liquid separation is sufficiently stirred, organic phase is washed with 25L saturated sodium bicarbonate solution, liquid separation after 25L water washing, and anhydrous magnesium sulfate is added
It dries, filters, after evaporating solvent under reduced pressure, is beaten with petroleum ether, dry, obtaining compound III-1 is faint yellow solid 3723.1g,
Yield 85.3%.1HNMR (400MHz, CDCl3), 8.26-8.25 (d, 2H), (7.78-7.58, m, 4H), 6.72-6.71 (d,
1H)。
The preparation of compound IV-1:
The THF solution of 2.5M LiHMDS (24360mL, 60.9mol, 10.0e.q.) is added in 50L bilayer kettle, 0 DEG C of drop
Add, the 10L tetrahydrofuran solution of 0 DEG C of dropwise addition compound III-1 (2000g, 6.09mol, 1.0e.q.), is stirred to react at 0 DEG C
3h is passed through CO2Gas, after being stirred to react 2h, LC-MS shows end of reaction.The saturation chlorination of 3L is slowly added dropwise in toward reaction solution
Aqueous ammonium quenching reaction.Dilute hydrochloric acid adjusts pH to 2, EA and extracts, and after water washing, liquid separation removes under reduced pressure molten after organic phase is dry
Agent, it is dry that compound IV-1 is yellow solid 1931.2g, yield 85.2%, purity 98% after petroleum ether mashing is added.
The preparation of compound V:
By compound IV-1 (1900g, 5.1mol, 1.0e.q.), 10L1,4- dioxane is added in 50L single layer kettle,
It finishes, at 0 DEG C, the tetrahydrofuran solution 5L of sodium tert-butoxide (1470g, 15.3mol, 3.0e.q.) is added dropwise, is added dropwise, at 0 DEG C
It is stirred to react 2h, LC-MS shows end of reaction.Reaction solution is added in dilute hydrochloric acid, a large amount of off-white powders are precipitated, are done after suction filtration
It is dry that compound V is faint yellow solid 1183g, it direct plunges into and reacts in next step.1HNMR (400MHz, DMSO-d6, δ ppm) and 13.5
(s, 1H), 7.21 (s, 1H).
The preparation of compound VI:
Compound V (1183g, 5.1mol, 1.0e.q.) is added in the reaction kettle of 50L, the methanol of 6L, 3.5L is added
Under water-bath, zinc powder (1667.4g, 25.5mol, 5e.q.) is added portionwise in DMF, ammonium chloride (818.4g, 15.3mol, 3e.q.),
It finishes, after being stirred to react 18h at 75 DEG C, LC-MS shows end of reaction.It filters, residue is first eluted with methanol, then uses methylene chloride
Elution, evaporating solvent under reduced pressure, raffinate is precipitated down to a large amount of yellow solids in the dilute hydrochloric acid of ice, are precipitated, after being sufficiently stirred, ethyl alcohol,
It is dry that compound VI is yellow solid 788.9g, two step yields 78.3% after petroleum ether is beaten respectively.1HNMR (400MHz,
DMSO-d6, δ ppm), 13.05 (s, 1H), 9.08 (s, 1H), 7.21 (s, 1H).The preparation of compound I:
In the single layer kettle of 50L, compound VI (788.9g, 3.99mol, 1.0e.q.) is added in the DMF of 7L, is added
Enter DIPEA (2580g, 19.96mol, 5.0e.q.), is added dropwise bromocyclopentane (2973.1g, 19.95mol, 5.0e.q.), 75
DEG C, it is stirred to react 16h.LC-MS shows end of reaction.Reaction solution is cooled to 40 DEG C, the tertiary ether of first is added, is filtered after stirring, is filtered
Liquid is down in ice water, the tertiary ether extraction of first, merges organic phase, washing, evaporating solvent under reduced pressure, is added methanol mashing, it is dry after change
Conjunction object I is yellow solid 1012.3g, yield 76%.1HNMR (400MHz, CDCl3, δ ppm) and 9.09 (s, 1H), 5.67-5.63
(t, 1H), 5.38-5.35 (m, 2H), 2.51-2.26 (m, 2H), 2.04-1.92 (m, 6H), 1.82-1.74 (m, 8H).(ESI-
TOF) m/z:[M+2]+calcd for C17H20ClN3O2: 333.82；Found:333；335.
Embodiment 4
The preparation of compound III-1:
In 50L bilayer kettle, compound II (2500g, 13.3mol, 1.0e.q.) is added in 20L Isosorbide-5-Nitrae-dioxane,
It being added DIPEA (2578.5g, 19.95mol, 1.5e.q.), DMAP (162.2g, 1.33mol, 0.1e.q.) is finished, at 0 DEG C,
It is added dropwise benzene sulfonyl chloride (2583.9g, 14.63mol, 1.1e.q.), 0~10 DEG C of temperature control, is added dropwise, 30 DEG C are stirred to react 5h,
LC-MS detects end of reaction.The water of 25L is added into reaction solution, rear liquid separation, organic phase 25L unsaturated carbonate hydrogen is sufficiently stirred
Sodium solution washs, liquid separation after 25L water washing, and anhydrous magnesium sulfate is added and dries, filters, after evaporating solvent under reduced pressure, is beaten with petroleum ether
Slurry, dry, obtaining compound III-1 is faint yellow solid 3810.5g, yield 87.3%.1HNMR (400MHz, CDCl3), 8.26-
8.25 (d, 2H), 7.78-7.58 (m, 4H), 6.72-6.71 (d, 1H).
The preparation of compound IV-1:
Diisopropylamine (616.7g, 6.09mol, 1.0e.q.) and 20L tetrahydrofuran are added in 50L bilayer kettle, -40 DEG C
It is added dropwise n-BuLi (2436mL, 6.09mol, 1.0e.q.), stirs 30min at 0 DEG C, the LDA produced is stand-by.Cool to -78
DEG C, the 10L tetrahydrofuran solution of compound III-1 (2000g, 6.09mol, 1.0e.q.) is added dropwise, is stirred to react at -100 DEG C
1h is passed through CO2Gas, is stirred to react 30min after adding, LC-MS shows end of reaction.The full of 3L is slowly added dropwise in toward reaction solution
With aqueous ammonium chloride solution quenching reaction.Dilute hydrochloric acid adjusts pH to 2, EA and extracts, after water washing, liquid separation, and after organic phase is dry, decompression
Solvent is evaporated off, it is dry that compound IV-1 is yellow solid 1820.1g, yield 80.3%, purity after petroleum ether mashing is added
98%.1HNMR (400MHz, DMSO-d6, δ ppm), 8.28-8.25 (d, 2H), 7.85-7.75 (m, 3H), 7.40 (s, 1H).
The preparation of compound V:
By compound IV-1 (1800g, 4.84mol, 1.0e.q.), 6L THF and 4L water is added in 50L single layer kettle, adds
Finish, at 0 DEG C, the aqueous solution 3L of LiOH (202.9g, 4.83mol, 1.0e.q.) is added dropwise, is added dropwise, is stirred to react at 40 DEG C
2h, LC-MS show end of reaction.Reaction solution is added in dilute hydrochloric acid, is precipitated a large amount of off-white powders, dry chemical combination after suction filtration
Object V is faint yellow solid 1010.7g, yield 90%.1HNMR (400MHz, DMSO-d6, δ ppm) and 13.5 (s, 1H), 7.21 (s,
1H)。
The preparation of compound VI:
Compound V (1010.7g, 4.36mol, 1.0e.q.) is added in the reaction kettle of 50L, the methanol of 8L, second is added
Sour (2618.3g, 43.6mol, 10e.q.), under water-bath, is added portionwise zinc powder (2851.1g, 43.6mol, 10e.q.), finishes,
After being stirred to react 28h at 50 DEG C, LC-MS shows end of reaction.It filtering, residue first elutes with methanol, then with eluent methylene chloride,
Evaporating solvent under reduced pressure, raffinate is precipitated down to a large amount of yellow solids in the dilute hydrochloric acid of ice, are precipitated, after being sufficiently stirred, ethyl alcohol, petroleum ether
It is dry that compound VI is yellow solid 605.6g, yield 70.3% after being beaten respectively.1HNMR (400MHz, DMSO-d6, δ
Ppm), 13.05 (s, 1H), 9.08 (s, 1H), 7.21 (s, 1H).
The preparation of compound I:
In the single layer kettle of 50L, compound VI (605.6g, 3.06mol, 1.0e.q.) is added in the DMA of 7L, is added
Enter TEA (1552.5g, 15.33mol, 5.0e.q.), is added dropwise bromocyclopentane (912.1g, 6.2mol, 2.0e.q.), 75 DEG C, stirs
Mix reaction 16h.LC-MS shows end of reaction.Reaction solution is cooled to 40 DEG C, the tertiary ether of first is added, is filtered after stirring, filtrate down to
In ice water, the tertiary ether of first is extracted, and merges organic phase, washing, and methanol mashing is added in evaporating solvent under reduced pressure, and the compound I after drying is
Yellow solid 674.2g, yield 66%.1HNMR (400MHz, CDCl3, δ ppm) and 9.09 (s, 1H), 5.67-5.63 (t, 1H),
5.38-5.35 (m, 2H), 2.51-2.26 (m, 2H), 2.04-1.92 (m, 6H), 1.82-1.74 (m, 8H).(ESI-TOF) m/z:
[M+2]+calcd for C17H20ClN3O2: 333.82；Found:333；335.
Embodiment 5
The preparation of compound VII:
Compound I (958.1g, 2.87mol, 1.0e.q.) is placed in the four-hole bottle of 20L, the tetrahydro furan of 2.0L is added
It mutters, at 50 DEG C, 16h is sufficiently stirred in the water of 6L, lithium hydroxide (240.9g, 5.74mol, 2.0e.q.), and LC-MS display has been reacted
Finish, concentrated hydrochloric acid tune PH to 2, there are a large amount of yellow solids to be precipitated, the tertiary ether mashing of first, filter compound VII is yellow solid
718.3g yield 94.2%.1HNMR (400MHz, DMSO-d6, δ ppm), 9.09 (s, 1H), 7.38 (s, 1H), 5.81-5.73
(m, 1H), 2.30-2.28 (m, 2H), 2.06-2.00 (m, 4H), 1.67-1.66 (m, 2H).The preparation of compound VIII:
In the four-hole bottle of 10L, compound VII (516g, 1.95mol, 1.0e.q.) is added in 3L DMF, 0 DEG C
Under, be added DIPEA (1004g, 7.8mol, 4.0e.q.), at -20 DEG C, be added portionwise HBTU (1479g, 3.9mol,
2.0e.q.), it is stirred to react 0.5h, at 5 DEG C, tetrahydrofuran solution (2.0M) 1.17L of dimethylamine is added dropwise, is stirred to react 1h,
LC-MS shows end of reaction.Reaction solution pours into the ice water of 9L, and after stirring, ethyl acetate extraction merges organic phase, saturated carbon
Acid sodium aqueous solution washing, water washing is dry after dilute hydrochloric acid washing, evaporating solvent under reduced pressure, and compound is filtered to obtain in petroleum ether mashing
VIII is yellow solid 416.8g, yield 73.1%.1HNMR (400MHz, CDCl3, δ ppm) and 1.63-1.66 (m, 2H), 1.95-
2.04 (m, 4H), 2.21-2.24 (m, 2H), 2.50 (s, 1H), 3.01-3.06 (d, 6H), 4.78-4.82 (m, 1H), 6.80 (s,
1H), 8.97 (s, 1H).(ESI-TOF) m/z:[M+2]+calcd for C14H17ClN4O:292.77；Found:292；294.
Embodiment 6
The preparation of compound VII:
Compound I (950.5g, 2.84mol, 1.0e.q.) is placed in the four-hole bottle of 20L, the tetrahydrofuran of 2L is added,
At 20 DEG C, 18h is sufficiently stirred in the water of 6L, sodium hydroxide (227.8g, 5.69mol, 2.0e.q.), and LC-MS shows end of reaction,
Concentrated hydrochloric acid tune PH to 2 has a large amount of yellow solids to be precipitated, the tertiary ether mashing of first, filter compound VII is yellow solid 719.1g,
Yield 95.3%.1HNMR (400MHz, DMSO-d6, δ ppm), 9.09 (s, 1H), 7.38 (s, 1H), 5.81-5.73 (m, 1H),
2.30-2.28 (m, 2H), 2.06-2.00 (m, 4H), 1.67-1.66 (m, 2H).The preparation of compound VIII:
In the four-hole bottle of 10L, compound VII (719.1g, 2.70mol, 1.0e.q.) is added in 6L DMF, 0 DEG C
Under, be added DIPEA (1399.2g, 10.83mol, 4.0e.q.), at -20 DEG C, be added portionwise HATU (2566.6g, 6.75mol,
2.5e.q.), it is stirred to react 0.5h, at 5 DEG C, dimethylamine methanol solution (2.5M) 1.62L is added dropwise, be stirred to react 1h, LC-MS is aobvious
Show end of reaction.Reaction solution pours into the ice water of 12L, and after stirring, ethyl acetate extraction merges organic phase, saturated sodium carbonate water
Solution washing, water washing, after dilute hydrochloric acid washing, dry, evaporating solvent under reduced pressure, petroleum ether mashing, filter compound VIII is
Yellow solid 617.4g, yield 78.1%.1HNMR (400MHz, CDCl3, δ ppm) and 1.63-1.66 (m, 2H), 1.95-2.04 (m,
4H), 2.21-2.24 (m, 2H), 2.50 (s, 1H), 3.01-3.06 (d, 6H), 4.78-4.82 (m, 1H), 6.80 (s, 1H),
8.97 (s, 1H).(ESI-TOF) m/z:[M+2]+calcd for C14H17ClN4O:292.77；Found:292；294.
Embodiment 7
The preparation of compound VII:
Compound I (1012.3g, 3.03mol, 1.0e.q.) is placed in the four-hole bottle of 20L, the tetrahydro furan of 4.0L is added
It mutters, at 20 DEG C, 18h is sufficiently stirred in the water of 6L, potassium hydroxide (510.4g, 9.10mol, 3.0e.q.), and LC-MS display has been reacted
Finish, concentrated hydrochloric acid tune PH to 2, there are a large amount of yellow solids to be precipitated, the tertiary ether mashing of first, filter compound VII is yellow solid
727.0g yield 90.3%.1HNMR (400MHz, DMSO-d6, δ ppm), 9.09 (s, 1H), 7.38 (s, 1H), 5.81-5.73
(m, 1H), 2.30-2.28 (m, 2H), 2.06-2.00 (m, 4H), 1.67-1.66 (m, 2H).The preparation of compound VIII:
In the four-hole bottle of 10L, compound VII (727.0g, 2.73mol, 1.0e.q.) is added in 6L DMF, 20
At DEG C, CDI (887.3g, 5.47mol, 2.0e.q.) is stirred to react 0.5h, at 5 DEG C, is added dropwise dimethylamine methanol solution (2.5M)
2.18L, is stirred to react 1h, and LC-MS shows end of reaction.Reaction solution pours into the ice water of 12L, after stirring, ethyl acetate extraction,
Merge organic phase, saturated aqueous sodium carbonate washing, water washing is dry after dilute hydrochloric acid washing, evaporating solvent under reduced pressure, petroleum ether
Mashing, filter compound VIII be yellow solid 399.6g, yield 50.3%.1HNMR (400MHz, CDCl3, δ ppm))
1.63-1.66 (m, 2H), 1.95-2.04 (m, 4H), 2.21-2.24 (m, 2H), 2.50 (s, 1H), 3.01-3.06 (d, 6H),
4.78-4.82 (m, 1H), 6.80 (s, 1H), 8.97 (s, 1H).(ESI-TOF) m/z:[M+2]+calcd for C14H17ClN4O:
292.77；Found:292；294.
Embodiment 8
The preparation of compound VII:
Compound I (674.2g, 2.02mol, 1.0e.q.) is placed in the four-hole bottle of 20L, Isosorbide-5-Nitrae-dioxy six of 4L is added
At 100 DEG C, 10h, LC-MS display reaction is sufficiently stirred in ring, the water of 6L, lithium hydroxide (211.9g, 5.05mol, 2.5e.q.)
Finish, concentrated hydrochloric acid tune PH to 2, there are a large amount of yellow solids to be precipitated, the tertiary ether mashing of first, filter compound VII is yellow solid
511.5g yield 95.3%.1HNMR (400MHz, DMSO-d6, δ ppm), 9.09 (s, 1H), 7.38 (s, 1H), 5.81-5.73
(m, 1H), 2.30-2.28 (m, 2H), 2.06-2.00 (m, 4H), 1.67-1.66 (m, 2H).
The preparation of compound VIII:
In the four-hole bottle of 10L, compound VII (511.5g, 1.93mol, 1.0e.q.) is added in 5L THF, 0 DEG C
Under, it is added DIPEA (997.8g, 7.72mol, 4.0e.q.), at 20 DEG C, is added EDCI (739.9g, 3.86mol, 2.0e.q.)
It is stirred to react 1h, at 5 DEG C, is added HOBt (521.6g, 3.86mol, 2.0e.q.), after stirring 30min, dimethylamine hydrochloric acid is added
Salt (472.1,5.79mol, 3.0e.q.), 10h is stirred to react at 70 DEG C, and LC-MS shows end of reaction.Reaction solution pours into 12L's
In ice water, after stirring, ethyl acetate extraction merges organic phase, saturated aqueous sodium carbonate washing, water washing, dilute hydrochloric acid washing
Afterwards, dry, evaporating solvent under reduced pressure, petroleum ether mashing, filter compound VIII is yellow solid 171.2g, yield 30.3%.1HNMR (400MHz, CDCl3, δ ppm) and 1.63-1.66 (m, 2H), 1.95-2.04 (m, 4H), 2.21-2.24 (m, 2H), 2.50
(s, 1H), 3.01-3.06 (d, 6H), 4.78-4.82 (m, 1H), 6.80 (s, 1H), 8.97 (s, 1H).(ESI-TOF) m/z:[M+
2]+calcd for C14H17ClN4O:292.77；Found:292；294.
Claims (13)
1. the compound of structure formula (I):
2. the preparation method of compound I in a kind of claim 1 characterized by comprising
Wherein: R1For benzenesulfonyl or p-toluenesulfonyl.
3. the preparation method of compound I according to claim 2, it is characterised in that: compound II prepare compound III
The step of in, acyl chlorides be benzene sulfonyl chloride or paratoluensulfonyl chloride；The alkali is sodium hydride, 1,8- diazabicyclo
[5.4.0] 11-7- alkene, triethylamine, diisopropyl ethyl amine or the N that catalytic amount is added in above-mentioned alkali, N-4- bis-
Methylamino pyridine.
4. the preparation method of compound I according to claim 2, it is characterised in that: compound III prepare compound IV
The step of in, the alkali be lithium diisopropylamine, two (trimethyl silicon substrate) lithium amides or two (trimethyl silicon substrate) amino
Sodium；Carbon dioxide is carbon dioxide gas or dry ice.
5. according to claim 2 or the preparation method of compound I as claimed in claim 4, it is characterised in that: compound III
In the step of prepare compound IV, range of reaction temperature is -100~0 DEG C；The molar ratio of compound III and alkali is 1: 1~1:
10。
6. the preparation method of compound I according to claim 2, it is characterised in that: the step of compound IV prepare compound V
In rapid, alkali is sodium methoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide, sodium tert-butoxide or potassium tert-butoxide；Range of reaction temperature 0~
40℃；The molar ratio of compound IV and alkali is 1: 1~1: 3.
7. the preparation method of compound I according to claim 2, it is characterised in that: the step of compound V prepare compound VI
In rapid, the acidic materials are ammonium chloride or acetic acid.
8. according to preparation method described in claim 2 or claim 7, it is characterised in that: compound V prepare compound
In the step of VI, 50~100 DEG C of range of reaction temperature；The molar ratio of compound V and reducing agent is 1: 5~1: 10.
9. preparation method according to claim 2, it is characterised in that: in the step of compound VI prepare compound I, institute
The alkali stated selects triethylamine, diisopropyl ethyl amine or cesium carbonate；50~100 DEG C of range of reaction temperature；Compound VI, alkali with
The molar ratio range of bromocyclopentane is 1: 2~5: 2~5.
10. the method for the compound I prepare compound VII in claim 1, it is characterised in that:
11. the method for the compound I prepare compound VIII in claim 1, it is characterised in that:
12. according to claim 10 or claim 11 described in preparation method, it is characterised in that: compound I preparationization
In the step of closing object VII, the alkali selects sodium hydroxide, potassium hydroxide or lithium hydroxide；Range of reaction temperature 20~100
℃。
13. in the step of preparation method according to claim 11, compound VII prepare compound VIII, alkali is selected
Diisopropyl ethyl amine, 11-7- alkene of 1,8- diazabicyclo [5.4.0] or triethylamine；Condensing agent selection carbonyl dimidazoles,
1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride, hexafluorophosphoric acid O- (7- azepine benzo triazol-1-yl)-N,
N, N ', N '-tetramethylurea or O- benzotriazole-tetramethylurea hexafluorophosphate；The reagent of dimethylamine selects dimethylamine first
Alcoholic solution, dimethylamine tetrahydrofuran solution, dimethylamine hydrochloride；Range of reaction temperature -20~50 DEG C.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030045536A1 (en) * | 2000-12-01 | 2003-03-06 | Castelhano Arlindo L. | Compounds specific to adenosine A1 receptors and uses thereof |
| CN105399743A (en) * | 2010-11-10 | 2016-03-16 | 诺华有限公司 | Salt(s) Of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic Acid Dimethylamide And Processes Of Making Thereof |
| CN105859726A (en) * | 2016-05-18 | 2016-08-17 | 南京富润凯德生物医药有限公司 | Method for selective dehalogenation in pyrimidine fused ring |
| CN106478641A (en) * | 2016-10-09 | 2017-03-08 | 杭州科巢生物科技有限公司 | The novel synthesis of Rui Boxini intermediate |
| CN107118215A (en) * | 2017-05-06 | 2017-09-01 | 青岛辰达生物科技有限公司 | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediates |
| CN107266451A (en) * | 2016-04-07 | 2017-10-20 | 上海医药工业研究院 | The preparation method of sharp cloth intermediate of auspicious cloth former times |
-
2018
- 2018-01-09 CN CN201810018397.5A patent/CN110016024B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030045536A1 (en) * | 2000-12-01 | 2003-03-06 | Castelhano Arlindo L. | Compounds specific to adenosine A1 receptors and uses thereof |
| CN105399743A (en) * | 2010-11-10 | 2016-03-16 | 诺华有限公司 | Salt(s) Of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic Acid Dimethylamide And Processes Of Making Thereof |
| CN107266451A (en) * | 2016-04-07 | 2017-10-20 | 上海医药工业研究院 | The preparation method of sharp cloth intermediate of auspicious cloth former times |
| CN105859726A (en) * | 2016-05-18 | 2016-08-17 | 南京富润凯德生物医药有限公司 | Method for selective dehalogenation in pyrimidine fused ring |
| CN106478641A (en) * | 2016-10-09 | 2017-03-08 | 杭州科巢生物科技有限公司 | The novel synthesis of Rui Boxini intermediate |
| CN107118215A (en) * | 2017-05-06 | 2017-09-01 | 青岛辰达生物科技有限公司 | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediates |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115703722A (en) * | 2021-08-03 | 2023-02-17 | 江苏国泰超威新材料有限公司 | Preparation method of N, N-dimethyl trifluoromethyl sulfonamide |
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