CN110128292A - A kind of synthetic method of Ozanimod intermediate 4- cyano indone - Google Patents
A kind of synthetic method of Ozanimod intermediate 4- cyano indone Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C253/00—Preparation of carboxylic acid nitriles
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
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- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Abstract
The present invention provides a kind of synthetic method of Ozanimod intermediate 4- cyano indone, synthetic method reaction is mild, and route is brief, and product is conducive to isolate and purify；Use the chemical substance being routinely easy to get, it avoids using poisonous reagent cyanide and expensive metallic catalyst, security risk when reducing storage and using, reduce the quality control difficulty of finished product, it also significantly reduces production cost and handles the cost of the three wastes, obtained finished product high income, purity is high.The synthetic method of 4- cyano indone of the present invention is smaller to environmental hazard, meets the requirement of Green Chemistry, large-scale production easy to accomplish.
Description
Technical field
The invention belongs to chemical pharmacy fields, and in particular to a kind of synthesis side of Ozanimod intermediate 4- cyano indone
Method.
Background technique
Multiple sclerosis (MS) is a kind of chronic inflammation demyelinate central nervous system disease, and there are about patients in the whole world
2300000 people.The disease be due to outside human immune system abnormal aggression nerve insulating layer and support construction --- myelin causes
Inflammation and associated injury.This damage can destroy the information interchange between brain and other positions of body, finally, nervous system sheet
Body situation can deteriorate, this process is irreversible at present.Patient symptom and sign can be very different, this depends on damage
The quantity of wound and impacted nerve.Some patientss may lose the ability of independent ambulation, and other patients then may be through
The prolonged paracmasis is gone through, does not occur new symptom.The average age of onset of multiple sclerosis is green generally at 20-40 years old
The main reason for non-wound disables in prime of life group.MS clinical classification mainly has: relapsing remitting MS, secondary Advancement Type MS, original
Send out Advancement Type MS and progress relapsing MS.
Relapsing remitting MS (RMS) is the MS of common type, it is characterized in that Relapse rate breaks out, is followed by existed apparent
The partially or completely paracmasis, symptom is partially or completely improved and without apparent progression of disease in the meantime.RMS accounts for about just
The 85% of patient's population proportion is examined, and Advancement Type MS accounts for about 10-15%.
Ao Zhamode (Ozanimod) be a kind of novel, oral, selective sphingosine-1-phosphate ester receptor 1 (S1P1) and
Receptor 5 (S1P5) regulator is just being exploited for panimmunity inflammation, including RMS, ulcerative colitis and Crow grace at present
Disease.Ozanimod is selectively believed to that the specific subset of activated lymphocyte is inhibited to migrate to inflammation portion in conjunction with S1P1
Attack of the immune system to neural myelin is alleviated to reduce the circulation T that can lead to anti-inflammatory activity and bone-marrow-derived lymphocyte level in position,
And it can still maintain immunosurveillance.Ozanimod selectively is considered to activate in central nervous system (CNS) in conjunction with S1P5
Specific cells, this is possible to the regeneration of enhancing myelin, and prevents cynapse defect, may finally prevent neurotrosis.
The chemical structural formula of Ozanimod is as follows:
As the 4- cyano indone of Ozanimod bulk pharmaceutical chemicals important intermediate, chemical structural formula are as follows:
Synthesis technology in relation to Ozanimod, existing literature report is less, and the synthesis in relation to intermediate 4- cyano indone
Route, it is reported in the literature just less, only it is seen in patent WO2011/60389A1 and other several documents.To sum up
The synthetic route of Ozanimod intermediate 4- cyano indone mainly has following 3:
1, the 4- cyano indone synthetic route of patent WO2011/60389A1 report are as follows:
2, other 4- cyano indone synthetic routes reported in the literature are as follows:
In summary 3 4- cyano indone synthetic routes, it is not difficult to find out that, 3 synthetic routes have used poisonous reagent cyanogen
Compound, for example zinc cyanide, hydrogenate cuprous and potassium cyanide etc., not only purchase requirement has a Special use qualification to these reagents, storage and
The requirement used is also very stringent, but no matter how to be strict with, and all there is huge security risks；And three-protection design is multiple
It is miscellaneous, it is at high cost, it is unfriendly to environment.In the 1st article of route, and use Pd compound as catalyst, it is not only expensive, more
It is difficult to remove the quality for totally increasing finished product control difficulty in finished product, yield is lower, so that entire synthesis technology is very
Difficult large-scale production.In the 2-3 articles route, cyanide is equally used, and have synthesis temperature higher, reaction is violent, instead
Long between seasonable, yield is low to wait unfavorable conditions.
Summary of the invention
To solve the above-mentioned problems, the present invention provides a kind of synthetic method of Ozanimod intermediate 4- cyano indone,
It includes the following steps:
Step 1: compound A, ethylene glycol and p-methyl benzenesulfonic acid, which are dissolved in organic solvent, reacts to obtain reaction solution, and reaction solution is mentioned
Compound B is obtained after pure；
Step 2: compound B being dissolved in organic solvent, n-BuLi is added and reacts to obtain reaction solution, reaction solution is purified
Compound C is obtained afterwards；
Step 3: compound C and hydroxylamine hydrochloride are dissolved in organic solvent, remove solvent after reaction, be added anhydrous formic acid,
Anhydrous sodium acetate and acetic anhydride acid anhydride, react to obtain reaction solution, and 4- cyano indone is obtained after reaction solution is purified.
Further,
In step 1, the molar ratio of the compound A, ethylene glycol and p-methyl benzenesulfonic acid are 1:1~4:0.01~0.16；Institute
The mass ratio for stating compound A and organic solvent is 1:5~10；
And/or in step 2, the molar ratio of the compound B and n-BuLi is 1:1~1.5；The compound B with have
The mass ratio of solvent is 1:1~5；
And/or in step 3, the compound C, hydroxylamine hydrochloride, anhydrous sodium acetate and acetic anhydride acid anhydride molar ratio be 1:
1~2:1~2:1~2；The mass ratio of the compound C and organic solvent, anhydrous formic acid is 1:5~10:5~10.
Further,
In step 1, the molar ratio of the compound A, ethylene glycol and p-methyl benzenesulfonic acid are 1:2:0.05；The compound A
Mass ratio with organic solvent is 1:6；
And/or in step 2, the molar ratio of the compound B and n-BuLi is 1:1.2；The compound B with it is organic
The mass ratio of solvent is 1:3；
And/or in step 3, the compound C, hydroxylamine hydrochloride, anhydrous sodium acetate and acetic anhydride acid anhydride molar ratio be 1:
1.1:1.2:1.5；The mass ratio of the compound C and organic solvent, anhydrous formic acid is 1:8:7.
Further,
In step 1, the organic solvent is toluene；
And/or in step 2, the organic solvent is tetrahydrofuran；
And/or in step 3, the organic solvent is ethyl alcohol.
Further,
In step 1, the reaction is to react 10~20 hours at 80~120 DEG C；
And/or in step 2, the addition n-BuLi is to be added dropwise, and the temperature of dropwise addition is -100~-70 DEG C；And/or step
In rapid 2, the reaction is to react 2~6 hours at -100~-70 DEG C；
And/or in step 3, the reaction temperature of the compound C and hydroxylamine hydrochloride is room temperature, and the reaction time is 1~4 small
When；And/or in step 3, reaction temperature is 50~80 DEG C after addition anhydrous formic acid, anhydrous sodium acetate and acetic anhydride acid anhydride, reaction
Time 8~15 hours.
Further,
In step 1, the reaction is to react 15 hours at 90 DEG C；
And/or in step 2, the temperature that n-BuLi is added is -80 DEG C；And/or in step 2, the reaction is
At -80 DEG C, react 4 hours；
And/or in step 3, the reaction temperature of the compound C and hydroxylamine hydrochloride is room temperature, and the reaction time is 3 hours；
And/or in step 3, reaction temperature is 60 DEG C after addition anhydrous formic acid, anhydrous sodium acetate and acetic anhydride acid anhydride, the reaction time 10
Hour.
Further,
In step 1, the purification is cooling, the stratification by reaction solution, except washing after sub-cloud solution, is filtered, decompression
Organic solvent is removed in concentration distillation；
And/or in step 2, the purification is washing reaction liquid, and filtering is concentrated under reduced pressure distillation and removes organic solvent；
And/or in step 3, to adjust reaction solution pH to 1~3, crystallization, filtering is dried under reduced pressure for the purification.
Further,
In step 1, for reaction solution is cooled to 10~30 DEG C, stratification uses hydrogen after removing sub-cloud solution for the purification
Sodium hydroxide solution and saturated common salt water washing, filtering are concentrated under reduced pressure distillation and remove organic solvent；
And/or in step 2, is with saturated salt solution washing reaction liquid, filtering distillation is concentrated under reduced pressure and has gone in the purification
Solvent；
And/or in step 3, to adjust reaction solution pH to 1~3, crystallization with dilute hydrochloric acid, filtering is depressurized dry for the purification
It is dry.
Further,
It is described that reaction solution is cooled to 20 DEG C in step 1；
And/or in step 3, reaction solution pH to 2 is adjusted with dilute hydrochloric acid.
Further,
The dilute hydrochloric acid concentration is 1N.
Room temperature refers to 25 DEG C ± 5 DEG C in the present invention.
4- cyano indone is to prepare the important intermediate of Ozanimod bulk pharmaceutical chemicals, meeting when producing the intermediate in the prior art
Use poisonous reagent cyanide and metallic catalyst.Poisonous reagent cyanide is there is huge security risk, and three-protection design
Complexity, it is at high cost, it is unfriendly to environment；Metallic catalyst is expensive, and is difficult to remove in finished product totally, increases end
The quality of product controls difficulty, and yield is lower.Meanwhile prepare 4- cyano indone in the prior art there is also synthesis temperatures it is higher,
The problems such as reaction is violent, and the reaction time is long.These problems are serious to affect 4- cyano indone large-scale production, influences it and answers
With.
The present invention provides a kind of synthetic method of Ozanimod intermediate 4- cyano indone, synthetic method reaction temperature
With, route is brief, product be conducive to isolate and purify；The chemical substance being routinely easy to get is used, is avoided using poisonous reagent cyaniding
Object and expensive metallic catalyst, security risk when reducing storage and using reduce the quality control of finished product
Difficulty also significantly reduces production cost and handles the cost of the three wastes, obtained finished product high income, purity is high.4- of the present invention
The synthetic method of cyano indone is smaller to environmental hazard, meets the requirement of Green Chemistry, large-scale production easy to accomplish.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Detailed description of the invention
Fig. 1 is Ozanimod intermediate 4- cyano indone prepared by embodiment 11HNMR map.
Fig. 2 is the MS map of Ozanimod intermediate 4- cyano indone prepared by embodiment 1.
Fig. 3 is the HPLC map of Ozanimod intermediate 4- cyano indone standard reference material.
Fig. 4 is the HPLC map of Ozanimod intermediate 4- cyano indone prepared by embodiment 1.
Fig. 5 is the HPLC map of Ozanimod intermediate 4- cyano indone prepared by embodiment 3.
Fig. 6 is the HPLC map of Ozanimod intermediate 4- cyano indone prepared by embodiment 5.
Specific embodiment
Raw material, equipment used in the specific embodiment of the invention are known product, are obtained by purchase commercial product.
The synthetic route of Ozanimod intermediate 4- cyano indone of the present invention are as follows:
Wherein, compound A is 4- bromindion, comes from Chengdu Wei Bang pharmaceutcal corporation, Ltd, lot number 20180201；
Compound B is the bromo- indan-1-one -1,2- ethylene ketal of 4-；
Compound C is 4- formoxyl indan-1-one -1,2- ethylene ketal.
The synthetic method of embodiment 1, Ozanimod intermediate 4- cyano indone of the present invention
Step 1: the synthesis of compound B (the bromo- indan-1-one -1,2- ethylene ketal of 4-)
The theoretical amount of the raw material and compound B that synthesize compound B is as shown in table 1.
Table 1 synthesizes the raw material of compound B and the theoretical amount of compound B
| Title | Molecular weight | Inventory (g) |
| 4- bromindion | 211.06 | 150.00 |
| Ethylene glycol | 62.07 | 88.23 |
| P-methyl benzenesulfonic acid | 172.2 | 6.12 |
| Toluene | 92.14 | 900.00 |
| Bromo- indan-1-one -1,2- the ethylene ketal of 4- | 255.11 | Theoretical amount: 181.3 |
900.00g toluene is added into reaction kettle, sequentially add the 4- bromindion of 150.00g, 88.23g ethylene glycol and
6.12g p-methyl benzenesulfonic acid is warming up to 90 DEG C, back flow reaction 15 hours.Reaction solution is cooled to 20 DEG C, stratification, under removing
After layer solution, with sodium hydroxide solution and saturated common salt water washing, filtering is concentrated under reduced pressure distillation and removes organic solvent, obtains the bromo- indenes of 4-
Full -1- ketone -1,2- ethylene ketal 169.3g, purity 99.1%, yield 93.4%.
Step 2: the synthesis of compound C (4- formoxyl indan-1-one -1,2- ethylene ketal)
The theoretical amount of the raw material and compound C that synthesize compound C is as shown in table 2.
Table 2 synthesizes the raw material of compound C and the theoretical amount of compound C
| Title | Molecular weight | Inventory (g) |
| Bromo- indan-1-one -1,2- the ethylene ketal of 4- | 255.11 | 110.00 |
| Tetrahydrofuran | 72.11 | 330.00 |
| N-BuLi | 64.06 | 33.15 |
| 4- formoxyl indan-1-one -1,2- ethylene ketal | 204.22 | Theoretical amount: 88.06 |
330.00g tetrahydrofuran is added into reaction kettle, bromo- indan-1-one -1, the 2- second two of 4- of 110.00g is added
Alcohol ketal is cooled to -80 DEG C, and 33.15g n-BuLi is added dropwise, and reacts 4 hours.By reaction solution with saturated common salt water washing, mistake
Filter is concentrated under reduced pressure distillation and removes organic solvent, obtains 4- formoxyl indan-1-one -1,2- ethylene ketal 84.1g, purity 99.2%,
Yield 95.5%.
The synthesis of step 3:Ozanimod intermediate (4- cyano indone)
The theoretical amount of the raw material and 4- cyano indone that synthesize 4- cyano indone is as shown in table 3.
Table 3 synthesizes the raw material of 4- cyano indone and the theoretical amount of 4- cyano indone
| Title | Molecular weight | Inventory (g) |
| 4- formoxyl indan-1-one -1,2- ethylene ketal | 204.22 | 80.00 |
| Ethyl alcohol | 46.07 | 640.00 |
| Hydroxylamine hydrochloride | 69.49 | 29.94 |
| Anhydrous formic acid | 46.03 | 560.00 |
| Anhydrous sodium acetate | 590.53 | 277.60 |
| Acetic anhydride acid anhydride | 102.09 | 59.99 |
| 4- cyano indone | 157.17 | Theoretical amount: 61.57 |
Under room temperature, the ethyl alcohol of 640.00g is added into reaction kettle, sequentially adds the 4- formoxyl indane -1- of 80.00g
Ketone -1,2- ethylene ketal and 29.94g hydroxylamine hydrochloride are stirred to react 3 hours.Reaction solution is concentrated under reduced pressure and removes solvent, is added
560.00g anhydrous formic acid, 277.60g anhydrous sodium acetate and 59.99g acetic anhydride acid anhydride are warming up to 60 DEG C, react 10 hours, will
Reaction solution adjusts pH=2, crystallization with dilute hydrochloric acid, and filtering is dried under reduced pressure, obtains 4- cyano indone 56.2g, purity 99.5%, yield
91.3%.
The synthetic method of embodiment 2, Ozanimod intermediate 4- cyano indone of the present invention
Step 1: the synthesis of compound B (the bromo- indan-1-one -1,2- ethylene ketal of 4-)
The theoretical amount of the raw material and compound B that synthesize compound B is as shown in table 4.
Table 4 synthesizes the raw material of compound B and the theoretical amount of compound B
750.00g toluene is added into reaction kettle, sequentially add the 4- bromindion of 150.00g, 44.11g ethylene glycol and
1.22g p-methyl benzenesulfonic acid is warming up to 90 DEG C, back flow reaction 15 hours.Reaction solution is cooled to 20 DEG C, stratification, under removing
After layer solution, with sodium hydroxide solution and saturated common salt water washing, filtering is concentrated under reduced pressure distillation and removes organic solvent, obtains the bromo- indenes of 4-
Full -1- ketone -1,2- ethylene ketal 162.1g, purity 99.1%, yield 89.4%.
Step 2: the synthesis of compound C (4- formoxyl indan-1-one -1,2- ethylene ketal)
The theoretical amount of the raw material and compound C that synthesize compound C is as shown in table 5.
Table 5 synthesizes the raw material of compound C and the theoretical amount of compound C
| Title | Molecular weight | Inventory (g) |
| Bromo- indan-1-one -1,2- the ethylene ketal of 4- | 255.11 | 110.00 |
| Tetrahydrofuran | 72.11 | 220.00 |
| N-BuLi | 64.06 | 27.62 |
| 4- formoxyl indan-1-one -1,2- ethylene ketal | 204.22 | Theoretical amount: 88.06 |
220.00g tetrahydrofuran is added into reaction kettle, bromo- indan-1-one -1, the 2- second two of 4- of 110.00g is added
Alcohol ketal is cooled to -80 DEG C, and 27.62g n-BuLi is added dropwise, and reacts 4 hours.By reaction solution with saturated common salt water washing, mistake
Filter is concentrated under reduced pressure distillation and removes organic solvent, obtains 4- formoxyl indan-1-one -1,2- ethylene ketal 81.5g, purity 99.2%,
Yield 92.6%.
The synthesis of step 3:Ozanimod intermediate (4- cyano indone)
The theoretical amount of the raw material and 4- cyano indone that synthesize 4- cyano indone is as shown in table 6.
Table 6 synthesizes the raw material of 4- cyano indone and the theoretical amount of 4- cyano indone
Under room temperature, the ethyl alcohol of 400.00g is added into reaction kettle, sequentially adds the 4- formoxyl indane -1- of 80.00g
Ketone -1,2- ethylene ketal and 27.22g hydroxylamine hydrochloride are stirred to react 3 hours.Reaction solution is concentrated under reduced pressure and removes solvent, is added
400.00g anhydrous formic acid, 231.33g anhydrous sodium acetate and 39.99g acetic anhydride acid anhydride are warming up to 60 DEG C, react 10 hours, will
Reaction solution adjusts pH=2, crystallization with dilute hydrochloric acid, and filtering is dried under reduced pressure, obtains 4- cyano indone 52.3g, purity 99.4%, yield
84.9%.
The synthetic method of embodiment 3, Ozanimod intermediate 4- cyano indone of the present invention
Step 1: the synthesis of compound B (the bromo- indan-1-one -1,2- ethylene ketal of 4-)
The theoretical amount of the raw material and compound B that synthesize compound B is as shown in table 7.
Table 7 synthesizes the raw material of compound B and the theoretical amount of compound B
| Title | Molecular weight | Inventory (g) |
| 4- bromindion | 211.06 | 150.00 |
| Ethylene glycol | 62.07 | 176.45 |
| P-methyl benzenesulfonic acid | 172.2 | 12.24 |
| Toluene | 92.14 | 1500.00 |
| Bromo- indan-1-one -1,2- the ethylene ketal of 4- | 255.11 | Theoretical amount: 181.3 |
1500.00g toluene is added into reaction kettle, 4- bromindion, the 176.45g ethylene glycol of 150.00g are sequentially added
With 12.24g p-methyl benzenesulfonic acid, it is warming up to 90 DEG C, back flow reaction 15 hours.Reaction solution is cooled to 10~30 DEG C, stratification,
After sub-cloud solution, with sodium hydroxide solution and saturated common salt water washing, filtering is concentrated under reduced pressure distillation and removes organic solvent, obtains
Bromo- indan-1-one -1, the 2- ethylene ketal 162.8g of 4-, purity 99.0%, yield 89.8%.
Step 2: the synthesis of compound C (4- formoxyl indan-1-one -1,2- ethylene ketal)
The theoretical amount of the raw material and compound C that synthesize compound C is as shown in table 8.
Table 8 synthesizes the raw material of compound C and the theoretical amount of compound C
| Title | Molecular weight | Inventory (g) |
| Bromo- indan-1-one -1,2- the ethylene ketal of 4- | 255.11 | 110.00 |
| Tetrahydrofuran | 72.11 | 440.00 |
| N-BuLi | 64.06 | 41.43 |
| 4- formoxyl indan-1-one -1,2- ethylene ketal | 204.22 | Theoretical amount: 88.06 |
440.00g tetrahydrofuran is added into reaction kettle, bromo- indan-1-one -1, the 2- second two of 4- of 110.00g is added
Alcohol ketal is cooled to -80 DEG C, and 41.43g n-BuLi is added dropwise, and reacts 4 hours.By reaction solution with saturated common salt water washing, mistake
Filter is concentrated under reduced pressure distillation and removes organic solvent, obtains 4- formoxyl indan-1-one -1,2- ethylene ketal 82.9g, purity 99.0%,
Yield 94.1%.
The synthesis of step 3:Ozanimod intermediate (4- cyano indone)
The theoretical amount of the raw material and 4- cyano indone that synthesize 4- cyano indone is as shown in table 9.
Table 9 synthesizes the raw material of 4- cyano indone and the theoretical amount of 4- cyano indone
| Title | Molecular weight | Inventory (g) |
| 4- formoxyl indan-1-one -1,2- ethylene ketal | 204.22 | 80.00 |
| Ethyl alcohol | 46.07 | 800.00 |
| Hydroxylamine hydrochloride | 69.49 | 54.44 |
| Anhydrous formic acid | 46.03 | 800.00 |
| Anhydrous sodium acetate | 590.53 | 462.66 |
| Acetic anhydride acid anhydride | 102.09 | 79.98 |
| 4- cyano indone | 157.17 | Theoretical amount: 61.57 |
Under room temperature, the ethyl alcohol of 800.00g is added into reaction kettle, sequentially adds the 4- formoxyl indane -1- of 80.00g
Ketone -1,2- ethylene ketal and 54.44g hydroxylamine hydrochloride are stirred to react 3 hours.Reaction solution is concentrated under reduced pressure and removes solvent, is added
800.00g anhydrous formic acid, 462.66g anhydrous sodium acetate and 79.98g acetic anhydride acid anhydride are warming up to 60 DEG C, react 10 hours, will
Reaction solution adjusts pH=2, crystallization with dilute hydrochloric acid, and filtering is dried under reduced pressure, obtains 4- cyano indone 55.6g, purity 99.2%, yield
90.3%.
The synthetic method of embodiment 4, Ozanimod intermediate 4- cyano indone of the present invention
Step 1: the synthesis of compound B (the bromo- indan-1-one -1,2- ethylene ketal of 4-)
The theoretical amount of the raw material and compound B that synthesize compound B is as shown in table 10.
Table 10 synthesizes the raw material of compound B and the theoretical amount of compound B
| Title | Molecular weight | Inventory (g) |
| 4- bromindion | 211.06 | 150.00 |
| Ethylene glycol | 62.07 | 88.23 |
| P-methyl benzenesulfonic acid | 172.2 | 6.12 |
| Toluene | 92.14 | 900.00 |
| Bromo- indan-1-one -1,2- the ethylene ketal of 4- | 255.11 | Theoretical amount: 181.3 |
900.00g toluene is added into reaction kettle, sequentially add the 4- bromindion of 150.00g, 88.23g ethylene glycol and
6.12g p-methyl benzenesulfonic acid is warming up to 80 DEG C, back flow reaction 10 hours.Reaction solution is cooled to 10 DEG C, stratification, under removing
After layer solution, with sodium hydroxide solution and saturated common salt water washing, filtering is concentrated under reduced pressure distillation and removes organic solvent, obtains the bromo- indenes of 4-
Full -1- ketone -1,2- ethylene ketal 159.5g, purity 98.5%, yield 88.0%.
Step 2: the synthesis of compound C (4- formoxyl indan-1-one -1,2- ethylene ketal)
The theoretical amount of the raw material and compound C that synthesize compound C is as shown in table 11.
Table 11 synthesizes the raw material of compound C and the theoretical amount of compound C
| Title | Molecular weight | Inventory (g) |
| Bromo- indan-1-one -1,2- the ethylene ketal of 4- | 255.11 | 110.00 |
| Tetrahydrofuran | 72.11 | 330.00 |
| N-BuLi | 64.06 | 33.15 |
| 4- formoxyl indan-1-one -1,2- ethylene ketal | 204.22 | Theoretical amount: 88.06 |
330.00g tetrahydrofuran is added into reaction kettle, bromo- indan-1-one -1, the 2- second two of 4- of 110.00g is added
Alcohol ketal is cooled to -100 DEG C, and 33.15g n-BuLi is added dropwise, and reacts 2 hours.By reaction solution with saturated common salt water washing, mistake
Filter is concentrated under reduced pressure distillation and removes organic solvent, obtains 4- formoxyl indan-1-one -1,2- ethylene ketal 78.4g, purity 98.9%,
Yield 89.0%.
The synthesis of step 3:Ozanimod intermediate (4- cyano indone)
The theoretical amount of the raw material and 4- cyano indone that synthesize 4- cyano indone is as shown in table 12.
Table 12 synthesizes the raw material of 4- cyano indone and the theoretical amount of 4- cyano indone
| Title | Molecular weight | Inventory (g) |
| 4- formoxyl indan-1-one -1,2- ethylene ketal | 204.22 | 80.00 |
| Ethyl alcohol | 46.07 | 640.00 |
| Hydroxylamine hydrochloride | 69.49 | 29.94 |
| Anhydrous formic acid | 46.03 | 560.00 |
| Anhydrous sodium acetate | 590.53 | 277.60 |
| Acetic anhydride acid anhydride | 102.09 | 59.99 |
| 4- cyano indone | 157.17 | Theoretical amount: 61.57 |
Under room temperature, the ethyl alcohol of 640.00g is added into reaction kettle, sequentially adds the 4- formoxyl indane -1- of 80.00g
Ketone -1,2- ethylene ketal and 29.94g hydroxylamine hydrochloride are stirred to react 1 hour.Reaction solution is concentrated under reduced pressure and removes solvent, is added
560.00g anhydrous formic acid, 277.60g anhydrous sodium acetate and 59.99g acetic anhydride acid anhydride are warming up to 50 DEG C, react 8 hours, will be anti-
Liquid is answered to adjust pH=2, crystallization with dilute hydrochloric acid, filtering is dried under reduced pressure, obtains 4- cyano indone 53.8g, purity 99.0%, yield
87.3%.
The synthetic method of embodiment 5, Ozanimod intermediate 4- cyano indone of the present invention
Step 1: the synthesis of compound B (the bromo- indan-1-one -1,2- ethylene ketal of 4-)
The theoretical amount of the raw material and compound B that synthesize compound B is as shown in table 13.
Table 13 synthesizes the raw material of compound B and the theoretical amount of compound B
900.00g toluene is added into reaction kettle, sequentially add the 4- bromindion of 150.00g, 88.23g ethylene glycol and
6.12g p-methyl benzenesulfonic acid is warming up to 120 DEG C, back flow reaction 20 hours.Reaction solution is cooled to 30 DEG C, stratification, under removing
After layer solution, with sodium hydroxide solution and saturated common salt water washing, filtering is concentrated under reduced pressure distillation and removes organic solvent, obtains the bromo- indenes of 4-
Full -1- ketone -1,2- ethylene ketal 165.0g, purity 99.0%, yield 91.0%.
Step 2: the synthesis of compound C (4- formoxyl indan-1-one -1,2- ethylene ketal)
The theoretical amount of the raw material and compound C that synthesize compound C is as shown in table 14.
Table 14 synthesizes the raw material of compound C and the theoretical amount of compound C
| Title | Molecular weight | Inventory (g) |
| Bromo- indan-1-one -1,2- the ethylene ketal of 4- | 255.11 | 110.00 |
| Tetrahydrofuran | 72.11 | 330.00 |
| N-BuLi | 64.06 | 33.15 |
| 4- formoxyl indan-1-one -1,2- ethylene ketal | 204.22 | Theoretical amount: 88.06 |
330.00g tetrahydrofuran is added into reaction kettle, bromo- indan-1-one -1, the 2- second two of 4- of 110.00g is added
Alcohol ketal is cooled to -70 DEG C, and 33.15g n-BuLi is added dropwise, and reacts 6 hours.By reaction solution with saturated common salt water washing, mistake
Filter is concentrated under reduced pressure distillation and removes organic solvent, obtains 4- formoxyl indan-1-one -1,2- ethylene ketal 78.8g, purity 99.0%,
Yield 89.5%.
The synthesis of step 3:Ozanimod intermediate (4- cyano indone)
The theoretical amount of the raw material and 4- cyano indone that synthesize 4- cyano indone is as shown in Table 15.
Table 15 synthesizes the raw material of 4- cyano indone and the theoretical amount of 4- cyano indone
Under room temperature, the ethyl alcohol of 640.00g is added into reaction kettle, sequentially adds the 4- formoxyl indane -1- of 80.00g
Ketone -1,2- ethylene ketal and 29.94g hydroxylamine hydrochloride are stirred to react 4 hours.Reaction solution is concentrated under reduced pressure and removes solvent, is added
560.00g anhydrous formic acid, 277.60g anhydrous sodium acetate and 59.99g acetic anhydride acid anhydride are warming up to 80 DEG C, react 15 hours, will
Reaction solution adjusts pH=2, crystallization with dilute hydrochloric acid, and filtering is dried under reduced pressure, obtains 4- cyano indone 55.3g, purity 99.1%, yield
89.8%.
Illustrate beneficial effects of the present invention below by way of test example.
The detection for the Ozanimod intermediate 4- cyano indone that test example 1, the present invention synthesize
Products obtained therefrom Ozanimod intermediate 4- cyano indone in Example 1 carries out hydrogen spectrum and Mass Spectrometer Method, obtains
's1HNMR and MS map is shown in Fig. 1 and Fig. 2 respectively.It is right1HNMR and MS map is parsed, and parsing result is as follows:
1HNMR spectrum analysis:1δ=8.16 (d, J=7.5Hz, 1H) H NMR (400MHz, DMSO), 7.94 (d, J=
7.7Hz, 1H), 7.63 (t, J=7.6Hz, 1H), 3.28-3.22 (m, 2H), 2.77-2.71 (m, 2H)
MS spectrum analysis: 157.2 [M+H]+
The 4- cyano indone that the embodiments of the present invention 1 are prepared1HNMR and MS map and 4- cyano indone standard
Reference substance1HNMR and MS map structure is almost the same, illustrates that 1 products obtained therefrom of the embodiment of the present invention is 4- cyano indone.
Example 1, embodiment 3, embodiment 5 prepare resulting 4- cyano indone and 4- cyano indone standard reference material one
It rises and carries out HPLC positioning, as a result see Fig. 3~6.The result shows that: main peak retention time is consistent under the same terms, illustrate embodiment 1,
Embodiment 3,5 products obtained therefrom of embodiment are consistent with 4- cyano indone standard reference material, are 4- cyano indone.
To sum up, the present invention provides a kind of synthetic method of Ozanimod intermediate 4- cyano indone, the synthetic method is anti-
Should be mild, route is brief, and product is conducive to isolate and purify；The chemical substance being routinely easy to get is used, is avoided using poisonous reagent
Cyanide and expensive metallic catalyst, security risk when reducing storage and using, reduce the quality of finished product
Difficulty is controlled, production cost is also significantly reduced and handles the cost of the three wastes, obtained finished product high income, purity is high.This hair
The synthetic method of bright 4- cyano indone is smaller to environmental hazard, meets the requirement of Green Chemistry, large-scale production easy to accomplish.
Claims (10)
1. a kind of synthetic method of Ozanimod intermediate 4- cyano indone, it is characterised in that: it includes the following steps:
Step 1: compound A, ethylene glycol and p-methyl benzenesulfonic acid, which are dissolved in organic solvent, reacts to obtain reaction solution, after reaction solution is purified
Obtain compound B；
Step 2: compound B is dissolved in organic solvent, n-BuLi is added and reacts to obtain reaction solution, after reaction solution is purified
Compound C；
Step 3: compound C and hydroxylamine hydrochloride being dissolved in organic solvent, remove solvent after reaction, anhydrous formic acid, anhydrous is added
Sodium acetate and acetic anhydride acid anhydride, react to obtain reaction solution, and 4- cyano indone is obtained after reaction solution is purified.
2. synthetic method according to claim 1, it is characterised in that:
In step 1, the molar ratio of the compound A, ethylene glycol and p-methyl benzenesulfonic acid are 1:1~4:0.01~0.16；Describedization
The mass ratio for closing object A and organic solvent is 1:5~10；
And/or in step 2, the molar ratio of the compound B and n-BuLi is 1:1~1.5；The compound B with it is organic molten
The mass ratio of agent is 1:1~5；
And/or in step 3, the compound C, hydroxylamine hydrochloride, anhydrous sodium acetate and acetic anhydride acid anhydride molar ratio be 1:1~
2:1~2:1~2；The mass ratio of the compound C and organic solvent, anhydrous formic acid is 1:5~10:5~10.
3. synthetic method according to claim 2, it is characterised in that:
In step 1, the molar ratio of the compound A, ethylene glycol and p-methyl benzenesulfonic acid are 1:2:0.05；The compound A with have
The mass ratio of solvent is 1:6；
And/or in step 2, the molar ratio of the compound B and n-BuLi is 1:1.2；The compound B and organic solvent
Mass ratio be 1:3；
And/or in step 3, the compound C, hydroxylamine hydrochloride, anhydrous sodium acetate and acetic anhydride acid anhydride molar ratio be 1:1.1:
1.2:1.5；The mass ratio of the compound C and organic solvent, anhydrous formic acid is 1:8:7.
4. described in any item synthetic methods according to claim 1~3, it is characterised in that:
In step 1, the organic solvent is toluene；
And/or in step 2, the organic solvent is tetrahydrofuran；
And/or in step 3, the organic solvent is ethyl alcohol.
5. synthetic method according to claim 1, it is characterised in that:
In step 1, the reaction is to react 10~20 hours at 80~120 DEG C；
And/or in step 2, the addition n-BuLi is to be added dropwise, and the temperature of dropwise addition is -100~-70 DEG C；And/or step 2
In, the reaction is to react 2~6 hours at -100~-70 DEG C；
And/or in step 3, the reaction temperature of the compound C and hydroxylamine hydrochloride is room temperature, and the reaction time is 1~4 hour；
And/or in step 3, reaction temperature is 50~80 DEG C after anhydrous formic acid, anhydrous sodium acetate and acetic anhydride acid anhydride is added, when reaction
Between 8~15 hours.
6. synthetic method according to claim 5, it is characterised in that:
In step 1, the reaction is to react 15 hours at 90 DEG C；
And/or in step 2, the temperature that n-BuLi is added is -80 DEG C；And/or in step 2, the reaction is -80
DEG C, it reacts 4 hours；
And/or in step 3, the reaction temperature of the compound C and hydroxylamine hydrochloride is room temperature, and the reaction time is 3 hours；With/
Or, reaction temperature is 60 DEG C after addition anhydrous formic acid, anhydrous sodium acetate and acetic anhydride acid anhydride, and the reaction time 10 is small in step 3
When.
7. synthetic method according to claim 1, it is characterised in that:
In step 1, the purification is cooling, the stratification by reaction solution, except washing after sub-cloud solution, filters, is concentrated under reduced pressure
Organic solvent is removed in distillation；
And/or in step 2, the purification is washing reaction liquid, and filtering is concentrated under reduced pressure distillation and removes organic solvent；
And/or in step 3, to adjust reaction solution pH to 1~3, crystallization, filtering is dried under reduced pressure for the purification.
8. synthetic method according to claim 7, it is characterised in that:
In step 1, for reaction solution is cooled to 10~30 DEG C, stratification uses hydroxide after removing sub-cloud solution for the purification
Sodium solution and saturated common salt water washing, filtering are concentrated under reduced pressure distillation and remove organic solvent；
And/or in step 2, the purification is with saturated salt solution washing reaction liquid, filtering, be concentrated under reduced pressure distillation go it is organic molten
Agent；
And/or in step 3, to adjust reaction solution pH to 1~3, crystallization with dilute hydrochloric acid, filtering is dried under reduced pressure, i.e., for the purification
It can.
9. synthetic method according to claim 8, it is characterised in that:
It is described that reaction solution is cooled to 20 DEG C in step 1；
And/or in step 3, reaction solution pH to 2 is adjusted with dilute hydrochloric acid.
10. synthetic method according to claim 9, it is characterised in that: the dilute hydrochloric acid concentration is 1N.
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| CN111704559A (en) * | 2020-06-30 | 2020-09-25 | 重庆医药高等专科学校 | Method for preparing 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile |
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