CN106928040A - The preparation method of SGLT2 inhibitor intermediate - Google Patents
The preparation method of SGLT2 inhibitor intermediate Download PDFInfo
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- CN106928040A CN106928040A CN201511026825.1A CN201511026825A CN106928040A CN 106928040 A CN106928040 A CN 106928040A CN 201511026825 A CN201511026825 A CN 201511026825A CN 106928040 A CN106928040 A CN 106928040A
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- 0 *c(cc1)cc(C(O)=O)c1Cl Chemical compound *c(cc1)cc(C(O)=O)c1Cl 0.000 description 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
Abstract
The invention provides a kind of preparation method of SGLT2 inhibitor intermediate II, comprise the following steps：Compound V carries out nucleophilic substitution in appropriate solvent and compound II is obtained with ethoxide reagent；Synthesis type is as follows：
Description
Technical field
The present invention relates to technical field of medicine synthesis, and in particular to the preparation method of antidiabetic drugs-SGLT2 inhibitor intermediate.
Background technology
The illness rate of diabetes is estimated in the World Health Organization (WHO) data display, global 18 one full year of life in 2014 and above adult
Evaluation is 9%, and be estimated to be within 2012 1500000 people directly causes death by diabetes, the lethal case hair of the diabetes more than 80%
Life is in low income and middle income country.The research and development of diabetes related treatments medicine are always the focus of medicament research and development.
On November 14th, 2012, the Forxiga that EU Committee's approval Bristol Myers Squibb and AstraZeneca are developed jointly
(dapagliflozin, Dapagliflozin) is used to treat diabetes B, and the medicine is with the white (Sodium of sodium glucose co-transporter 2
Glucose co-transporters, referred to as SGLT-2) it is first medicine of action target spot, Dapagliflozin and its double with diformazan
The compound preparation of guanidine composition also successively ratifies listing in USA and EU.Additionally, as SGLT-2 inhibitor medicaments, Pfizer
The Sotagliflozin of the Ertugliflozin and Lexicon drugmakers research and development of research and development is all in the third stage stage.
These three compounds are glycosyl and are bonded by β-C- aryl glycosides with aryl side chains and connect, and include identical aryl side chains.
The synthetic method of the document report side chain has the following two kinds at present, and this two methods all refers to Fu Ke acylation reactions and carbonyl reduction is anti-
Should.
Route one：The synthetic route of intermediate 1 of patent WO03099836 reports is as follows：
The route with the bromo- 2- chlorobenzoic acids of 5- (compound III a) as raw material, a of intermediate IV is obtained with oxalyl chloride reaction, then with benzene
Ether is obtained intermediate II a through Fu Ke acylation reactions, is then reduced with triethyl silicane and BFEE and intermediate I a is obtained.
The shortcoming of the method is when preparing intermediate II a, Fu Ke acylation reactions occur by a of intermediate IV and phenetole and occurs in phenetole
The ortho isomer by-products content that obtains of ortho position be up to more than 12%, it is extremely difficult that post processing removes the ortho isomer impurity；
The patent report step reaction yield is 64%, and the purity that intermediate II a is obtained is not reported.
Route two：The synthetic method of intermediate 5 of patent WO2013152476 reports is similar with above-mentioned route one, as follows：
With the iodo- 2- chlorobenzoic acids of 5-, (compound III b) is obtained the b of intermediate IV, with benzene second to the route as raw material with oxalyl chloride reaction
Ether is obtained intermediate II b through Fu Ke acylation reactions, then is obtained with polymethyl hydrogen siloxane and alchlor reduction intermediate II b middle
The b of body I.Intermediate I b is similar with intermediate I a structures, and the synthetic method of this route two is similar with above-mentioned route one, synthesizes
The b of intermediate IV is also passed through in journey Fu Ke acylation reactions occur with phenetole, equally also produced and largely occurred to exist by Fu Ke acylation reactions
Ortho isomer obtained from the adjacent base position of phenetole, post processing purifying is also extremely difficult.Additionally, intermediate is obtained in the patent
The purity of II b is not also reported.
Those skilled in the art know, with the above-mentioned a of synthetic method prepare compound II and compound ii b, a large amount of ortho position isomeries of generation
Body is inevitable, and ortho isomer and target compound polarity are closely, is difficult to remove by means such as recrystallizations, should
Class isomers introduces subsequent reactions and can participate in the new impurity of reaction generation again.It is, thus, sought for the conjunction high of new regioselectivity
Into a of method prepare compound II and compound ii b, and make it industrialized production.
The content of the invention
Technical problem solved by the invention is to solve about preparing showing for the chloro- 3- of 4- (4- ethoxyl phenenyls) aminomethyl phenyl halides
Have in technology and there is a problem of that building-up process produces more isomers and post processing purifying comparatively laborious, there is provided a kind of new 4- chlorine
The preparation method of -3- (4- ethoxyl phenenyls) aminomethyl phenyl halides II.
Idea of the invention is that such：With the chloro- 3- carboxyl phenyls halides (compound III) of 4- for raw material prepare compound V,
Then nucleophilic substitution is carried out in appropriate solvent with ethoxide reagent and compound II is obtained, so as to avoid ortho position isomery
The generation of body.
The invention provides the synthesis technique or preparation method of a kind of SGLT2 inhibitor intermediate II, comprise the following steps：
A), the chloro- benzoic acid of 5- halos -2- (compound III) carries out acylation reaction and obtains compound V with fluorobenzene；
B), compound V and ethoxide reagent carry out nucleophilic substitution in appropriate solvent and compound II are obtained；
Synthetic route is as follows：
Wherein, the X in described compound III structure is selected from Br or I.
As for step 1), the implementation for referring to patent WO2011039107 reports is obtained.
The invention provides a kind of preparation method of SGLT2 inhibitor intermediate I, comprise the following steps：
B), compound V and ethoxide reagent carry out nucleophilic substitution in appropriate solvent and compound II are obtained；
Synthetic route is as follows：
Wherein, the X in described compound V structure is selected from Br or I.
It is a kind of preferred embodiment in, in the step b), ethoxide reagent used can be caustic alcohol, potassium ethoxide,
Lithium ethoxide, magnesium ethylate, preferred alcohol sodium, potassium ethoxide, lithium ethoxide.
In a preferred embodiment, in the step b), reaction dissolvent be selected from tetrahydrofuran, 2- methyltetrahydrofurans,
Nitromethane, acetonitrile, DMF (being abbreviated as DMF), dimethyl sulfoxide (being abbreviated as DMSO), preferably DMF
And DMSO.
It is a kind of preferred embodiment in, in the step b), compound V is with the molar ratio of ethoxide reagent
0.9:1~1:8, preferably 1:1~1:3.
It is a kind of preferred embodiment in, the reaction temperature of the step b) is -10 DEG C~80 DEG C, preferably 0 DEG C~40 DEG C.
It is a kind of preferred embodiment in, reaction time of the step b) is 0.5 hour (being abbreviated as h)~10h.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can obtain final product the present invention more preferably real in any combination
Example.
Unless otherwise specified, the reagent and raw material used by the present invention are commercially available.
The advantage of the invention is that：The method of bibliography WO2011039107 reports is obtained compound V, the step reaction yield
Up to more than 94%, reaction selectivity is also very high, and the corresponding ortho isomer of generation is considerably less, is post-processed by crystallization and just may be used
Remove.Subsequent compound V can be prepared by compound II with ethoxide reagent nucleo philic substitution reaction, and post processing is fairly simple,
Reaction yield is up to more than 82%, and product purity is more than 99%.
This synthetic route preferably solves the problems, such as in document report synthetic route that isomers is more and is difficult to purify.Operation letter
Just, agents useful for same is cheap and easy to get, and does not have isomers in prepared product.This route is more suitable for industrialized production.
Specific embodiment
Hereinafter the present invention, but the protection domain being not intended to limit the invention will be expanded on further by specific embodiment.Do not taking off
On the premise of present inventive concept, those skilled in the art can be changed to preparation method and being made using instrument within the scope of the claims
Enter, these improvement also should be regarded as protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be with appended claims
It is defined.
In following embodiments, unless otherwise indicated, the bar that described test method is generally advised according to normal condition or manufacturer
Part is implemented；Shown raw material, reagent can be obtained by way of commercially available purchase.
The preparation of embodiment 1, (the iodo- 2- chlorphenyls of 5-) (4- fluorophenyls) ketone (compound Vb)
DCM (100mL), DMF (0.175g, 0.02eq) are added in the iodo- 2- chlorobenzoic acids (33.895g, 120mmol) of 5-,
Stirring, is slowly added dropwise oxalyl chloride (12.3mL, 1.2eq), reacts 2h after completion of dropping at room temperature, is concentrated under reduced pressure and removes solvent,
DCM (100mL) is added, fluorobenzene (17.298g, 1.5eq) is added, AlCl is added under ice bath3(17.6g, 1.1eq),
3h is reacted after adding at room temperature, TLC detects that slowly add water (100mL) under ice bath after completion of the reaction, extracted after stirring, has
Machine is mutually washed with 10%NaCl (50mL), and organic phase is concentrated under reduced pressure to obtain pale yellow oil, plus isopropanol (100mL),
Add water (100mL), stirring and crystallizing 2h under ice bath, suction filtration, filter cake isopropanol/water (1:1) mixed solution (20mL) is washed
Wash, the off-white powder 42.1g of dry compound Vb, yield：97.31%, purity：99.17%.Fusing point：69.2~70.4 DEG C.
ESI-MS(m/z)：358.99[M-H]-。1H NMR(600MHz,CDCl3):δ 7.84~7.82 (m, 2H), 7.76~7.74 (dd,
J=1.8,8.4Hz, 1H), 7.67 (d, J=1.8Hz, 1H), 7.21~7.19 (d, J=8.4Hz, 1H), 7.17~7.14 (t, J=8.4Hz, 2H).
The preparation of embodiment 2, (the bromo- 2- chlorphenyls of 5-) (4- fluorophenyls) ketone (compound Va)
DCM (70mL), DMF (0.132g, 0.03eq) are added in the bromo- 2- chlorobenzoic acids (14.128g, 60mmol) of 5-,
Stirring, is slowly added dropwise oxalyl chloride (5.6mL, 1.1eq), reacts 3h after completion of dropping at room temperature, and be concentrated under reduced pressure to obtain faint yellow oil
Shape thing, adds DCM (70mL), adds fluorobenzene (5.766g, 1eq), and AlCl is added under ice bath3(8g, 1eq), adds
React 5h at room temperature afterwards, TLC detects that slowly add water (70mL) under ice bath after completion of the reaction, extracted after stirring, organic phase
Washed with 10%NaCl (50mL), organic phase is concentrated under reduced pressure to obtain pale yellow oil, addition isopropanol (70mL) adds water
(70mL), stirring and crystallizing 2h under ice bath, suction filtration, filter cake isopropanol/water (1:1) mixed solution (20mL) washing,
The faint yellow solid 17.817g of dry compound Va, yield：94.7%, purity：99.12%.Fusing point：89.3~91 DEG C.
EI-MS(m/z)：312[M]+。1H NMR(600MHz,CDCl3):δ 7.85~7.82 (m, 2H), 7.57~7.55 (dd, J=2.4,
8.0Hz, 1H), 7.50 (d, J=2.4Hz, 1H), 7.34~7.33 (d, J=8.4Hz, 1H), 7.17~7.14 (t, J=8.4Hz, 2H).
The preparation of embodiment 3, (the iodo- 2- chlorphenyls of 5-) (4- ethoxyl phenenyls) ketone (compound IIb)
DMF (90mL) is added in (the iodo- 2- chlorphenyls of 5-) (4- fluorophenyls) ketone (18.03g, 50mmol), it is slow under ice bath
Caustic alcohol (3.74g, 1.1eq) is added, stirring reaction 1.5h at room temperature after adding, TLC is detected after completion of the reaction, under ice bath
Slowly added water (180mL), stirring and crystallizing 1h, suction filtration, and filter cake is washed with water (200mL), is beaten with ethanol (50mL)
Slurry, suction filtration, the faint yellow solid 16.72g of dry compound IIb, yield：86.5%, purity：99.53%.Fusing point：
100.8~101.9 DEG C.EI-MS(m/z)：386[M]+。1H NMR(400MHz,CDCl3):δ 7.77~7.75 (d, J=9.6Hz, 2H),
7.73~7.70 (dd, J=2.4,8.4Hz, 1H), 7.66~7.65 (d, J=2Hz, 1H), 7.19~7.17 (d, J=8.4Hz, 1H),
6.94~6.92 (d, J=9.2Hz, 2H), 4.14~4.09 (q, J=7.2Hz, 2H), 1.46~1.43 (t, J=6.8Hz, 3H).
The preparation of embodiment 4, (the iodo- 2- chlorphenyls of 5-) (4- ethoxyl phenenyls) ketone (compound IIb)
DMF (90mL) is added in (the iodo- 2- chlorphenyls of 5-) (4- fluorophenyls) ketone (18.03g, 50mmol), it is slow under ice bath
Potassium ethoxide (5.47g, 1.3eq) is added, stirring reaction 1h at 40 DEG C after adding, TLC is detected after completion of the reaction, delayed under ice bath
Slowly added water (180mL), stirring and crystallizing 1h, suction filtration, and filter cake is washed with water (200mL), is beaten with ethanol (50mL),
Suction filtration, the faint yellow solid 16.86g of dry compound IIb, yield：87.2%, purity：99.27%.
The preparation of embodiment 5, (the iodo- 2- chlorphenyls of 5-) (4- ethoxyl phenenyls) ketone (compound IIb)
DMSO (80mL) is added in (the iodo- 2- chlorphenyls of 5-) (4- fluorophenyls) ketone (18.03g, 50mmol), is delayed under ice bath
Slow to add lithium ethoxide (3.12g, 1.2eq), stirring reaction 3h at 0 DEG C after adding, TLC is detected after completion of the reaction, under ice bath
Slowly added water (240mL), stirring and crystallizing 1h, suction filtration, and filter cake is washed with water (200mL), is beaten with ethanol (50mL)
Slurry, suction filtration, the faint yellow solid 15.99g of dry compound IIb, yield：82.7%, purity：99.44%.
The preparation of embodiment 6, (the bromo- 2- chlorphenyls of 5-) (4- ethoxyl phenenyls) ketone (compound IIa)
DMF (90mL) is added in (the bromo- 2- chlorphenyls of 5-) (4- fluorophenyls) ketone (18.03g, 50mmol), it is slow under ice bath
Caustic alcohol (3.74g, 1.1eq) is added, stirring reaction 1h at room temperature after adding, TLC is detected after completion of the reaction, is delayed under ice bath
Slowly added water (180mL), stirring and crystallizing 1h under ice bath, suction filtration, and filter cake is washed with water (200mL), with ethanol (50mL)
Mashing, suction filtration, the faint yellow solid 14.47g of dry compound IIa, yield：85.2%, purity：99.38%.Fusing point：
72~73 DEG C.EI-MS(m/z)：338[M]+。1H NMR(400MHz,CDCl3):δ 7.77~7.75 (d, J=9.2Hz, 2H),
7.54~7.52 (dd, J=2.4,8.4Hz, 1H), 7.48 (d, J=2.4Hz, 1H), 7.33~7.31 (d, J=8.4Hz, 1H), 6.95~6.91 (d,
J=9.2Hz, 2H), 4.14~4.09 (q, J=6.8Hz, 2H), 1.47~1.43 (t, J=6.8Hz, 3H).
Claims (8)
- The preparation method of 1.SGLT2 inhibitor intermediate IIs, comprises the following steps：B), compound V and ethoxide reagent exist Nucleophilic substitution is carried out in appropriate solvent compound II is obtained；Synthesis type is as follows：Wherein, the X in described compound V structure is selected from Br or I.
- 2. preparation method according to claim 1, it is characterised in that also include step before the step b)：A), chemical combination Thing III carries out acylation reaction and obtains compound V with fluorobenzene；Synthesis type is as follows：Wherein, the X in described compound III structure is selected from Br or I.
- 3. preparation method according to claim 1 and 2, it is characterised in that the compound V passes through following steps a) chemical combination Thing III carries out acylation reaction and prepares with fluorobenzene；Synthesis type is as follows：Wherein, the X in described compound III structure is accordingly selected from Br or I.
- 4. preparation method according to claim 1 and 2, it is characterised in that in the step b), ethoxide examination used Agent can be caustic alcohol, potassium ethoxide, lithium ethoxide, magnesium ethylate, preferred alcohol sodium, potassium ethoxide, lithium ethoxide.
- 5. preparation method according to claim 1 and 2, it is characterised in that in the step b), the appropriate solvent is selected from Tetrahydrofuran, 2- methyltetrahydrofurans, nitromethane, acetonitrile, preferably DMF, DMSO, DMF and DMSO.
- 6. preparation method according to claim 1 and 2, it is characterised in that in the step b), compound V and ethyoxyl The molar ratio of metal reagent is 0.9:1~1:8, preferably 1:1~1:3.
- 7. preparation method according to claim 1 and 2, it is characterised in that in the step b), reaction temperature is -10 DEG C~ 80 DEG C, preferably 0 DEG C~40 DEG C.
- 8. preparation method according to claim 1 and 2, it is characterised in that the reaction time is 0.5h~10h in the step b).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108752184A (en) * | 2018-04-28 | 2018-11-06 | 杭州科耀医药科技有限公司 | A kind of preparation method of SGLT2 inhibitor intermediate |
| CN114044739A (en) * | 2022-01-12 | 2022-02-15 | 苏州开元民生科技股份有限公司 | Synthetic method for preparing 5-bromo-2-chloro-4' -ethoxy diphenylmethane |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108752184A (en) * | 2018-04-28 | 2018-11-06 | 杭州科耀医药科技有限公司 | A kind of preparation method of SGLT2 inhibitor intermediate |
| CN108752184B (en) * | 2018-04-28 | 2021-11-16 | 杭州科耀医药科技有限公司 | Preparation method of SGLT2 inhibitor intermediate |
| CN114044739A (en) * | 2022-01-12 | 2022-02-15 | 苏州开元民生科技股份有限公司 | Synthetic method for preparing 5-bromo-2-chloro-4' -ethoxy diphenylmethane |
| CN114044739B (en) * | 2022-01-12 | 2022-04-05 | 苏州开元民生科技股份有限公司 | Synthetic method for preparing 5-bromo-2-chloro-4' -ethoxy diphenylmethane |
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