CN108409626A - The preparation method of ovarian cancer resistance medicament Rucaparib key intermediates - Google Patents
The preparation method of ovarian cancer resistance medicament Rucaparib key intermediates Download PDFInfo
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- CN108409626A CN108409626A CN201810185280.6A CN201810185280A CN108409626A CN 108409626 A CN108409626 A CN 108409626A CN 201810185280 A CN201810185280 A CN 201810185280A CN 108409626 A CN108409626 A CN 108409626A
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- rucaparib
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- ovarian cancer
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- 0 *c1c(cc[n]2)c2cc(F)c1 Chemical compound *c1c(cc[n]2)c2cc(F)c1 0.000 description 1
- QOEAMLSLLJPIRF-UHFFFAOYSA-N Cc(c([N+]([O-])=O)cc(F)c1)c1C(OC)=O Chemical compound Cc(c([N+]([O-])=O)cc(F)c1)c1C(OC)=O QOEAMLSLLJPIRF-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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Abstract
The preparation method of ovarian cancer resistance medicament Rucaparib key intermediates, is related to the preparation of medicine intermediate.Compound 1 is using methanol and hexamethylene as solvent, and using p-methyl benzenesulfonic acid as catalyst, compound 2 is obtained after reaction；Using acetic acid and acetic anhydride as solvent, by compound 2 and nitric acid nak response, compound 3 is obtained；Compound 3 is solvent with N, N dimethylformamide dimethyl acetals, and triethylamine is catalyst, and reaction obtains compound 4；For compound 4 using methanol as solvent, Raney's nickel is catalyst, and reaction obtains compound 5, i.e. ovarian cancer resistance medicament Rucaparib key intermediates：6 fluorine 1H indazoles, 4 methyl formate.Nitric-sulfuric acid nitration reaction and waste water and gas is avoided to discharge, safety and environmental protection.Raw material is easy to get, and price is low, and raising reaction yield is convenient for industrialized production.
Description
Technical field
The present invention relates to the preparation of medicine intermediate, especially a kind of ovarian cancer resistance medicament Rucaparib key intermediates
Preparation method.
Background technology
Rucaparib obtains " breakthrough treatment " qualification in 2015 in the U.S., as single therapy BRCA (breast
Cancer susceptibility gene breast cancer susceptibility gene mutations) advanced ovarian cancer, be first acquisition qualification
Poly adenosine diphosphate-ribose polymerase-1 (PARP) inhibitor.
Poly adenosine diphosphate-ribose polymerase-1 (PARP) is a kind of DNA damage detection enzyme, is withered with cell in DNA damage reparation
Die middle performance key effect.Multiple studies have shown that PARP is the good target spot for treating tumour.
And Rucaparib is set out by its key intermediate can synthesize final products through six steps, as follows：
It is inquired according to the reaction of scifinder, does not find the correlation of the fluoro- 1H- indazoles -4- methyl formates of compound 6- specially
Profit, only document (Organic Process Research＆Development, 16 (12), a 1897-1904；
2012.Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP
Inhibitor), it is the synthesis pertinent literature of Rucaparib.Synthetic route (Routine of Synthesis) is as follows：
Document sulfuric acid and nitric acid mixed acid nitrification, cause a large amount of acid waste waters, exhaust emission；Esterification is catalyzed with sulfuric acid
Agent, sulfuric acid dosage is big, and wastewater flow rate is big；In the synthesis of the fluoro- 1H- indazoles -4- methyl formates of 6-, a large amount of Pd/C is used to be catalyzed
Agent, cost is very high, is purified using column chromatography, and efficiency is low.Overall yield of reaction is relatively low.
Invention content
The purpose of the present invention is to provide the fluoro- 1H- indazoles -4- first of key intermediate 6- of easy economic rucaparib
Sour methyl esters avoids mixed acid nitrification, raw material simplicity from being easy to get, and greatly reduces cost, the high ovarian cancer resistance medicament of reaction yield
The preparation method of Rucaparib key intermediates.
The present invention includes the following steps：
1) compound 1 is using methanol and hexamethylene as solvent, and using p-methyl benzenesulfonic acid as catalyst, compound 2 is obtained after reaction, is changed
Close object 1 and 2 general formula be respectively：
In step 1), the condition of the reaction can react 4~10h at 40~70 DEG C at reflux, and filtering is insoluble
Object, precipitation.
2) using acetic acid and acetic anhydride as solvent, by compound 2 and nitric acid nak response, compound 3, the general formula of compound 3 are obtained
For：
In step 2), the condition of the reaction can be that 2~10h is reacted at -10~20 DEG C；Powder can be used in the potassium nitrate
Last shape potassium nitrate；It is preferred that reacting 2~6h at 0~20 DEG C；The molar ratio of the compound 2 and potassium nitrate can be 1 ︰ (1.0~
1.5)。
3) for compound 3 with n,N-Dimethylformamide dimethylacetal (DMF-DMA) for solvent, triethylamine is catalyst,
Reaction, obtains compound 4, and the anti-general formula for closing object 4 is：
In step 3), the condition of the reaction can react 4~12h at 60~120 DEG C, be diluted with water, dichloromethane
Extraction, concentration；The compound 3 and the molar ratio of N,N-dimethylformamide dimethylacetal can be 1 ︰ (1.2~2.5).
4) for compound 4 using methanol as solvent, Raney's nickel is catalyst, and reaction obtains compound 5, i.e. ovarian cancer resistance medicament
Rucaparib key intermediates：The fluoro- 1H- indazoles -4- methyl formates of 6-, the general formula of compound 5 are：
In step 4), the condition of the reaction can be 0~40 DEG C under hydrogen, reaction 4 under normal pressure to 20 atmospheric pressure~
24h；The condition of reaction reacts 4~for 24 hours preferably to be passed through hydrogen under 25~50 DEG C, normal pressure to 10 atmospheric pressure, filtering,
Add water, refilters to obtain crude product, methanol/water is recrystallized to give yellow solid, i.e. ovarian cancer resistance medicament Rucaparib is crucial intermediate
Body：The fluoro- 1H- indazoles -4- methyl formates of 6-.
The present invention reaction route be：
Compared with prior art, beneficial effects of the present invention are：
1) the invention avoids nitric-sulfuric acid nitration reactions, avoid waste water and gas discharge, safety and environmental protection.
2) the raw material price that is easy to get is low, at low cost, is convenient for industrialized production；
3) reaction yield is substantially increased, purifying products step is simplified, is conducive to industrialized production.
Specific implementation mode
The present invention is further illustrated for following embodiment.
Embodiment 1
Step 1：Compound 1 (15.4g, 0.1mol) is dissolved in the in the mixed solvent of 100mL methanol and 100mL hexamethylenes,
P-methyl benzenesulfonic acid monohydrate (0.95g, 0.005mol) is added, reflux water-dividing reacts 4h, then filters, and removes insoluble matter, subtracts
Pressure distillation precipitation, obtains faint yellow solid 19g, is directly used in the next step without further purification.
Step 2：Compound 1 (19g, 0.1mol) is dissolved in 80mL acetic acid and 50mL acetic anhydride, 0 DEG C is cooled to, by powder
The potassium nitrate (10.1g, 0.1mol) of shape is added portionwise, and reacts 2h after adding, is filtered to remove insoluble matter, reaction solution is poured into
In 400mL ice water, filter, it is dry, obtain 16g compounds 2.
Step 3：Compound 2 (16g, 0.075mol) is added to DMF-DMA, and (n,N-Dimethylformamide dimethyl contracts
Aldehyde) in (10.7g, 0.09mol), triethylamine (7.6g, 0.075mol) is added, is heated to 60 DEG C, reacts 4h, 200mL water is added,
Dichloromethane extracts, and detaches organic layer, dry, is concentrated to give the crude product 22g of compound 3, it is anti-to be directly used in lower step without further purification
It answers.
Step 4：Compound 3 (22g, 0.075mol) is dissolved in 200mL methanol, 2.2g Raney's nickel catalysts are added, is led to
Enter hydrogen, at 25 DEG C, 4h is reacted under normal pressure, Filtration of catalyst is added 300mL water, crude product is obtained by filtration, crude product is through first
Alcohol/water is recrystallized to give the fluoro- 1H- indazoles -4- methyl formates of 6.9g yellow solids 6-.
Embodiment 2
Step 1：Compound 1 (15.4g, 0.1mol) is dissolved in the in the mixed solvent of 100mL methanol and 100mL hexamethylenes,
P-methyl benzenesulfonic acid monohydrate (0.95g, 0.005mol) is added, reflux water-dividing reacts 10h, then filters, and removes insoluble matter,
It is evaporated under reduced pressure precipitation, faint yellow solid 19.5g is obtained, is directly used in the next step without further purification.
Step 2：Compound 1 (19.5g, 0.1mol) is dissolved in 80mL acetic acid and 50mL acetic anhydride, is cooled to 10 DEG C, it will
Powdered potassium nitrate (15.2g, 0.15mol) is added portionwise, and reacts 6h after adding, is filtered to remove insoluble matter, reaction solution is fallen
Enter in 400mL ice water, filters, it is dry, obtain 17.3g compounds 2.
Step 3：Compound 2 (17.3g, 0.081mol) is added to DMF-DMA (n,N-Dimethylformamide dimethyl
Acetal) in (23.8g, 0.20mol), triethylamine (8.2g, 0.081mol) is added, is heated to 100 DEG C, reacts 12h, is added
200mL water, dichloromethane extraction detach organic layer, dry, are concentrated to give the crude product 23.7g of compound 3, without further purification directly
For the next step.
Step 4：Compound 3 (23.7g, 0.081mol) is dissolved in 200mL methanol, 2.4g Raney's nickel catalysts are added,
It is passed through hydrogen, at 40 DEG C, is reacted for 24 hours under 10 atmospheric pressure, Filtration of catalyst, 300mL water is added, is obtained by filtration thick
Product, crude product are recrystallized to give the fluoro- 1H- indazoles -4- methyl formates of 7.1g yellow solids 6- through methanol/water.
Embodiment 3
Step 1：Compound 1 (15.4g, 0.1mol) is dissolved in the in the mixed solvent of 100mL methanol and 100mL hexamethylenes,
P-methyl benzenesulfonic acid monohydrate (0.95g, 0.005mol) is added, reflux water-dividing reacts 6h, then filters, and removes insoluble matter, subtracts
Pressure distillation precipitation, obtains faint yellow solid 18.8g, is directly used in the next step without further purification.
Step 2：Compound 1 (18.8,0.1mol) is dissolved in 80mL acetic acid and 50mL acetic anhydride, 20 DEG C are cooled to, by powder
The potassium nitrate (12.1g, 0.12mol) of last shape is added portionwise, and reacts 4h after adding, is filtered to remove insoluble matter, reaction solution is poured into
In 400mL ice water, filter, it is dry, obtain 16.2g compounds 2.
Step 3：Compound 2 (16.2g, 0.076mol) is added to DMF-DMA (n,N-Dimethylformamide dimethyl
Acetal) in (17.9g, 0.15mol), triethylamine (7.7g, 0.076mol) is added, is heated to 80 DEG C, reacts 8h, 200mL is added
Water, dichloromethane extraction detach organic layer, dry, are concentrated to give the crude product 22.6g of compound 3, are directly used in down without further purification
Step reaction.
Step 4：Compound 3 (22.6g, 0.076mol) is dissolved in 200mL methanol, 2.3g Raney's nickel catalysts are added,
It is passed through hydrogen, at 30 DEG C, 12h is reacted under 5 atmospheric pressure, Filtration of catalyst is added 300mL water, crude product is obtained by filtration,
Crude product is recrystallized to give the fluoro- 1H- indazoles -4- methyl formates of 6.7g yellow solids 6- through methanol/water.
The invention avoids nitric-sulfuric acid nitration reactions, avoid waste water and gas discharge, safety and environmental protection.Raw material is easy to get price
It is low, it is at low cost, it is convenient for industrialized production；Reaction yield is substantially increased, purifying products step is simplified, is conducive to industrial metaplasia
Production.
Claims (10)
1. the preparation method of ovarian cancer resistance medicament Rucaparib key intermediates, it is characterised in that include the following steps：
1) compound 1 is using methanol and hexamethylene as solvent, and using p-methyl benzenesulfonic acid as catalyst, compound 2, compound are obtained after reaction
1 and 2 general formula is respectively：
2) using acetic acid and acetic anhydride as solvent, by compound 2 and nitric acid nak response, compound 3 is obtained, the general formula of compound 3 is：
3) for compound 3 with n,N-Dimethylformamide dimethylacetal (DMF-DMA) for solvent, triethylamine is catalyst, reaction,
Compound 4 is obtained, the anti-general formula for closing object 4 is：
4) for compound 4 using methanol as solvent, Raney's nickel is catalyst, and reaction obtains compound 5, i.e. ovarian cancer resistance medicament
Rucaparib key intermediates：The fluoro- 1H- indazoles -4- methyl formates of 6-, the general formula of compound 5 are：
2. the preparation method of ovarian cancer resistance medicament Rucaparib key intermediates as described in claim 1, it is characterised in that in step
It is rapid 1) in, the condition of the reaction is to react 4~10h at 40~70 DEG C at reflux, filters insoluble matter, precipitation.
3. the preparation method of ovarian cancer resistance medicament Rucaparib key intermediates as described in claim 1, it is characterised in that in step
It is rapid 2) in, the condition of the reaction is that 2~10h is reacted at -10~20 DEG C.
4. the preparation method of ovarian cancer resistance medicament Rucaparib key intermediates as claimed in claim 3, it is characterised in that described
The condition of reaction is that 2~6h is reacted at 0~20 DEG C；
5. the preparation method of ovarian cancer resistance medicament Rucaparib key intermediates as described in claim 1, it is characterised in that in step
It is rapid 2) in, the potassium nitrate use powdered potassium nitrate.
6. the preparation method of ovarian cancer resistance medicament Rucaparib key intermediates as described in claim 1, it is characterised in that in step
It is rapid 2) in, the molar ratio of the compound 2 and potassium nitrate is 1 ︰ (1.0~1.5).
7. the preparation method of ovarian cancer resistance medicament Rucaparib key intermediates as described in claim 1, it is characterised in that in step
It is rapid 3) in, the condition of the reaction reacts 4~12h at 60~120 DEG C, is diluted with water, dichloromethane extraction, concentration.
8. the preparation method of ovarian cancer resistance medicament Rucaparib key intermediates as described in claim 1, it is characterised in that in step
It is rapid 3) in, the molar ratio of the compound 3 and n,N-Dimethylformamide dimethylacetal is 1 ︰ (1.2~2.5).
9. the preparation method of ovarian cancer resistance medicament Rucaparib key intermediates as described in claim 1, it is characterised in that in step
It is rapid 4) in, the condition of the reaction is 0~40 DEG C under hydrogen, reaction 4 under normal pressure to 20 atmospheric pressure~for 24 hours；The condition of reaction
Preferably to be passed through hydrogen, react 4 under 25~50 DEG C, normal pressure to 10 atmospheric pressure~for 24 hours, filtering adds water, refilters to obtain
Crude product, methanol/water are recrystallized to give yellow solid, i.e. ovarian cancer resistance medicament Rucaparib key intermediates：The fluoro- 1H- Yin of 6-
Azoles -4- methyl formates.
10. the preparation method of ovarian cancer resistance medicament Rucaparib key intermediates as described in claim 1, it is characterised in that its
Reaction route is：
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180687A (en) * | 2018-08-31 | 2019-01-11 | 山东轩德医药科技有限公司 | A kind of preparation method of auspicious Kappa step intermediate |
| CN109824677A (en) * | 2019-04-03 | 2019-05-31 | 江苏开元药业有限公司 | The preparation method for treating ovarian cancer Rui Kapabu |
| WO2023013974A1 (en) * | 2021-08-03 | 2023-02-09 | 고려대학교 산학협력단 | Novel method for producing rucaparib that is parp inhibitor and intermediate thereof |
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| CN102212028A (en) * | 2010-04-06 | 2011-10-12 | 上海恩翊医药科技有限公司 | Preparation method of (L)-5-hydroxytryptophan |
| CN106749282A (en) * | 2017-01-25 | 2017-05-31 | 青岛辰达生物科技有限公司 | A kind of preparation method for treating ovarian cancer Rucaparib intermediates |
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2018
- 2018-03-07 CN CN201810185280.6A patent/CN108409626A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212028A (en) * | 2010-04-06 | 2011-10-12 | 上海恩翊医药科技有限公司 | Preparation method of (L)-5-hydroxytryptophan |
| CN106749282A (en) * | 2017-01-25 | 2017-05-31 | 青岛辰达生物科技有限公司 | A kind of preparation method for treating ovarian cancer Rucaparib intermediates |
Non-Patent Citations (1)
| Title |
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| ADAM T. GILLMORE ET AL.: "Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor", 《ORG. PROCESS RES. DEV. 》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180687A (en) * | 2018-08-31 | 2019-01-11 | 山东轩德医药科技有限公司 | A kind of preparation method of auspicious Kappa step intermediate |
| CN109824677A (en) * | 2019-04-03 | 2019-05-31 | 江苏开元药业有限公司 | The preparation method for treating ovarian cancer Rui Kapabu |
| CN109824677B (en) * | 2019-04-03 | 2021-09-03 | 江苏开元药业有限公司 | Preparation method of medicine Ruipafeb for treating ovarian cancer |
| WO2023013974A1 (en) * | 2021-08-03 | 2023-02-09 | 고려대학교 산학협력단 | Novel method for producing rucaparib that is parp inhibitor and intermediate thereof |
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Application publication date: 20180817 |