CN106966912A - (R) preparation method of 3 amino butanols - Google Patents
(R) preparation method of 3 amino butanols Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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Abstract
The present invention relates to pharmaceutical intermediate synthesis technical field, a kind of preparation method of the amino butanol of Du Lutewei intermediates (R) 3 is specifically disclosed, is with 3（Boc amino）Butyric acid is initiation material, and type I compound is obtained by chiral resolution；Again the compound of formula II is obtained by sodium borohydride and lewis acid reduction；Last amino deprotection obtains (R) 3 amino butanol.Raw material used in the inventive method is cheap and easy to get, and reaction condition is gentle, and security is reliable, and technology stability is good, high income, and optical purity is high, and environmental protection is suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical intermediate synthesis technical field.
Background technology
Du Lutewei, also known as De Luogewei, English name：Dolutegravir, trade name：Tivicay, is by Britain's system
Medicine giant's GlaxoSmithKline PLC（GSK）With Japanese Shionogi company（Shionogi）A kind of anti-AIDS of cooperative development is new
Medicine.
(R) -3- amino butanols are the important intermediates for synthesizing Du Lutewei, and its structural formula is as follows：
。
Prior art prepare the problem of intermediate is present be mainly reflected in it is following some：Reaction scheme is longer, overall to receive
Rate is low, and technological operation is harsher, needs to use toxic articles and explosive sensitive materials.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of (R) -3- amino butanols, with reaction scheme
Short, mild condition, safe and reliable, technology stability are good, energy consumption is low, high income the advantages of, obtained (R) -3- amino butanols
Optical purity is high, and the inventive method environmental protection is suitable for industrialized production.
In order to solve the above technical problems, the technical solution used in the present invention is：(R) preparation method of -3- amino butanols,
Comprise the following steps：
S1, with 3-（T-butoxycarbonyl-amino）Butyric acid is raw material, and its chiral resolution is obtained into type I compound；
S2, by type I compound sodium borohydride and lewis acid reduction obtain the compound of formula II；
S3, the compound of formula II is sloughed into tertbutyloxycarbonyl obtain (R) -3- amino butanols；
Reaction equation is as follows：
。
Further, the step S1 chiral resolutions include：
By 3-（T-butoxycarbonyl-amino）Butyric acid is dissolved in organic solvent, under agitating and heating state, preferably controls temperature 40~75
DEG C, add resolving agent thereto, insulated and stirred for a period of time, is cooled to 10~15 DEG C, suction filtration, dry carboxylate；
Gained carboxylate is added in ethanol, 70~75 DEG C are heated to, after insulation a period of time, 10~15 DEG C are cooled to, suction filtration,
Dry, repeat this operation, until gained carboxylate ee values are more than 99%；
It is finally that carboxylate is soluble in water, concentrated hydrochloric acid is added, its pH value is adjusted to 1~2, is extracted with ethyl acetate, organic phase is dense
It is reduced to no cut and obtains type I compound.
Wherein, the organic solvent is methanol, acetone or alcohol；The resolving agent is S- phenyl ethylamines, S- naphthalene ethylamines or L-
Ephedrine, is preferably added to the resolving agent and 3-（T-butoxycarbonyl-amino）The mol ratio of butyric acid is 0.7~0.9:1.
Further, the step S2 includes：
Gained type I compound is dissolved in tetrahydrofuran, 0~20 DEG C of temperature control adds sodium borohydride, then Louis is added portionwise
Acid, is finished, and temperature is risen into 25~50 DEG C, insulation reaction；
After completion of the reaction, add water and be quenched, organic phase is concentrated into no cut, be recrystallized to give the compound of formula II.
Optionally, the lewis acid is zinc chloride, lithium chloride or elemental iodine.
Further, the step S3 includes：
The compound of gained formula II is dissolved in dichloromethane, trifluoroacetic acid is slowly added dropwise into system for 0~10 DEG C of temperature control, be incubated
Track to raw material conversion to finish, then sodium hydroxide is added portionwise, system pH is adjusted to 9~10, filtered, concentration, distillation is obtained
(R) -3- amino butanols.
It is using the beneficial effect produced by above-mentioned technical proposal：The inventive method has that reaction scheme is short, condition temperature
With, safe and reliable, technology stability is good, energy consumption is low, high income the advantages of, obtained (R) -3- amino butanol optical purities
It is high.The inventive method environmental protection, is suitable for industrialized production, particularly suitable for the preparation of Du Lutewei intermediates.
Embodiment
The present invention provides a kind of preparation method of Du Lutewei intermediates (R) -3- amino butanols, is with 3-（Boc- amino）
Butyric acid is initiation material, and type I compound is obtained by chiral resolution；
Again the compound of formula II is obtained by sodium borohydride and lewis acid reduction；
Last amino deprotection obtains (R) -3- amino butanols.
Illustrate below and the inventive method is described in further detail.
Embodiment 1
By 20.3 g 3-（Boc- amino）Butyric acid is dissolved in 40.6 mL methanol, is heated with stirring to 40~50 DEG C, at such a temperature
10.2 mL methanol solutions of 9.1 g S- phenyl ethylamines are slowly added dropwise, drop finishes, and the min of insulated and stirred 20~30 slowly cools to 10
~15 DEG C, suction filtration, dry the g of carboxylate 14；Then 14 g carboxylates are added in 28 mL ethanol, are heated to 70~75 DEG C,
15~20 min are incubated, 10~15 DEG C are slowly dropped to, suction filtration, dry the g of carboxylate 13 repeats this operation 2 times, obtains carboxylic acid
Salt 12.2 g, ee value 99.7%；Finally 12.2 g carboxylates are added in 36 mL water, pH is adjusted to 1~2, addition with concentrated hydrochloric acid
30 mL ethyl acetate are extracted twice, and are merged organic phase and are concentrated into no cut, obtain the g of type I compound 7.6.
Embodiment 2
By 30 g 3-（Boc- amino）Butyric acid is dissolved in 60 mL ethanol, is heated with stirring to 70~75 DEG C, at such a temperature slowly
15 mL ethanol solutions of 14 g S- phenyl ethylamines are added dropwise, drop finishes, and the min of insulated and stirred 20~30 slowly cools to 10~15 DEG C,
Suction filtration, dry the g of carboxylate 21.6；Then 21.6 g carboxylates are added in 43.2 mL ethanol, is heated to 70~75 DEG C, guarantor
15~20 min of temperature, are slowly dropped to 10~15 DEG C, suction filtration, dry the g of carboxylate 20, repeat this operation 2 times, obtain carboxylate
18.8 g, ee value 99.6%；Finally 18.8 g carboxylates are added in 55 mL water, pH is adjusted to 1~2 with concentrated hydrochloric acid, 50 are added
ML ethyl acetate is extracted twice, and is merged organic phase and is concentrated into no cut, obtains the g of type I compound 11.7.
Embodiment 3
By 50 g 3-（Boc- amino）Butyric acid is dissolved in 150 mL acetone, is heated with stirring to 40~50 DEG C, at such a temperature slowly
50 mL acetone solns of 20.9 g S- phenyl ethylamines are added dropwise, drop finishes, and the min of insulated and stirred 20~30 slowly cools to 10~15
DEG C, suction filtration, dry the g of carboxylate 36；Then 36 g carboxylates are added in 72 mL ethanol, is heated to 70~75 DEG C, insulation
15~20 min, are slowly dropped to 10~15 DEG C, suction filtration, dry the g of carboxylate 33.8, repeat this operation 2 times, obtain carboxylate
32 g, ee value 99.7%；Finally 32 g carboxylates are added in 96 mL water, pH is adjusted to 1~2 with concentrated hydrochloric acid, 80 mL second are added
Acetoacetic ester is extracted twice, and is merged organic phase and is concentrated into no cut, obtains the g of type I compound 19.6.
Embodiment 4
By 50 g 3-（Boc- amino）Butyric acid is dissolved in 150 mL acetone, is heated with stirring to 40~50 DEG C, at such a temperature slowly
50 mL acetone solns of 23.9 g S- phenyl ethylamines are added dropwise, drop finishes, and the min of insulated and stirred 20~30 slowly cools to 10~15
DEG C, suction filtration, dry the g of carboxylate 37.2；Then 37.2 g carboxylates are added in 75 mL ethanol, are heated to 70~75 DEG C,
15~20 min are incubated, 10~15 DEG C are slowly dropped to, suction filtration, dry the g of carboxylate 34.7 repeats this operation 2 times, obtains carboxylic
Hydrochlorate 33.3 g, ee value 99.8%；Finally 33.3 g carboxylates are added in 100 mL water, pH is adjusted to 1~2 with concentrated hydrochloric acid, plus
Enter 85 mL ethyl acetate to be extracted twice, merge organic phase and be concentrated into no cut, obtain the g of type I compound 20.5.
Embodiment 5
By 50 g 3-（Boc- amino）Butyric acid is dissolved in 150 mL acetone, is heated with stirring to 40~50 DEG C, at such a temperature slowly
50 mL acetone solns of 26.9 g S- phenyl ethylamines are added dropwise, drop finishes, and the min of insulated and stirred 20~30 slowly cools to 10~15
DEG C, suction filtration, dry the g of carboxylate 38；Then 38 g carboxylates are added in 75 mL ethanol, is heated to 70~75 DEG C, insulation
15~20 min, are slowly dropped to 10~15 DEG C, suction filtration, dry the g of carboxylate 35.2, repeat this operation 2 times, obtain carboxylate
33.8 g, ee value 99.5%；Finally 33.8 g carboxylates are added in 100 mL water, pH is adjusted to 1~2 with concentrated hydrochloric acid, 85 are added
ML ethyl acetate is extracted twice, and is merged organic phase and is concentrated into no cut, obtains the g of type I compound 20.8.
Embodiment 6
By 71 g 3-（Boc- amino）Butyric acid is dissolved in 142 mL methanol, is heated with stirring to 40~50 DEG C, at such a temperature slowly
35.5 mL methanol solutions of 47.8 g S- naphthalene ethylamines are added dropwise, drop finishes, and the min of insulated and stirred 20~30 slowly cools to 10~15
DEG C, suction filtration, dry the g of carboxylate 59；Then 59 g carboxylates are added in 148 mL ethanol, is heated to 70~75 DEG C, insulation
15~20 min, are slowly dropped to 10~15 DEG C, suction filtration, dry the g of carboxylate 56.6, repeat this operation 2 times, obtain carboxylate
52 g, ee value 99.8%；Finally 52 g carboxylates are added in 156 mL water, pH is adjusted to 1~2 with concentrated hydrochloric acid, 130 mL are added
Ethyl acetate is extracted twice, and is merged organic phase and is concentrated into no cut, obtains the g of type I compound 27.9.
Embodiment 7
By 90 g 3-（Boc- amino）Butyric acid is dissolved in 225 mL ethanol, is heated with stirring to 70~75 DEG C, at such a temperature slowly
60 mL ethanol solutions of 58.5 g L- ephedrines are added dropwise, drop finishes, and the min of insulated and stirred 20~30 slowly cools to 10~15
DEG C, suction filtration, dry the g of carboxylate 78.5.Then 78.5 g carboxylates are added in 200 mL ethanol, are heated to 70~75 DEG C,
15~20 min are incubated, 10~15 DEG C are slowly dropped to, suction filtration, dry the g of carboxylate 75.3 repeats this operation 2 times, obtains carboxylic
Hydrochlorate 69.2 g, ee value 99.7%；Finally 69.2 g carboxylates are added in 195 mL water, pH is adjusted to 1~2 with concentrated hydrochloric acid, plus
Enter 150 mL ethyl acetate to be extracted twice, merge organic phase and be concentrated into no cut, obtain the g of type I compound 37.1.
Embodiment 8
115 g type I compounds are dissolved in 460 mL tetrahydrofurans, ice bath is cooled to 0~10 DEG C, then 23.7 g boron are added portionwise
Sodium hydride, 0~10 DEG C of temperature control, then 230 mL tetrahydrofuran solutions of 165.4 g iodines are slowly added dropwise into system, drop finishes,
It is gradually heating to 25~30 DEG C, liquid phase tracks to raw material conversion and finished, 60 mL water quenchings is added dropwise and go out reaction, is concentrated under reduced pressure into nothing and evaporates
Point, 500 mL methanol are added, are warming up to after 55~60 DEG C of dissolved clarifications, 0.5 h is incubated, 1050 mL water is added dropwise at such a temperature, are dripped
Finish, the h of insulated and stirred 1, then be slowly dropped to 15~20 DEG C, suction filtration dries to obtain the g of II compound of formula 97.4, yield 91%.
Embodiment 9
85 g type I compounds are dissolved in 600 mL tetrahydrofurans, ice bath is cooled to 0~10 DEG C, then 20.2 g boron are added portionwise
Sodium hydride, 0~10 DEG C of temperature control, then 113.9 g zinc chloride are added portionwise into system, drip and finish, be gradually heating to 25~30 DEG C, liquid
Mutually track to raw material conversion to finish, 45 mL saturated ammonium chlorides are added dropwise reaction is quenched, be concentrated under reduced pressure into no cut, add 350 mL1
Mol/L aqueous hydrochloric acid solutions and the extraction of 510 mL ethyl acetate, aqueous phase are extracted with 170 mL ethyl acetate again, merge organic phase, dense
Contracting, adds 350 mL methanol, is warming up to after 55~60 DEG C of dissolved clarifications, is incubated 0.5 h, and 880 mL water are added dropwise at such a temperature, and drop finishes,
The h of insulated and stirred 1, then it is slowly dropped to 15~20 DEG C, suction filtration dries to obtain the g of II compound of formula 70.2, yield 88.7%.
Embodiment 10
100 g type I compounds are dissolved in 700 mL tetrahydrofurans, ice bath is cooled to 0~10 DEG C, then 24.6 g boron are added portionwise
Sodium hydride, 0~10 DEG C of temperature control, then 46 g lithium chlorides are added portionwise into system, drip and finish, be gradually heating to 25~30 DEG C, liquid phase
Track to raw material conversion to finish, 55 mL saturated ammonium chlorides are added dropwise reaction is quenched, be concentrated under reduced pressure into no cut, add 400 mL1
Mol/L aqueous hydrochloric acid solutions and the extraction of 600 mL ethyl acetate, aqueous phase are extracted with 200 mL ethyl acetate again, merge organic phase, dense
Contracting, adds 350 mL methanol, is warming up to after 55~60 DEG C of dissolved clarifications, is incubated 0.5 h, and 950 mL water are added dropwise at such a temperature, and drop finishes,
The h of insulated and stirred 1, then it is slowly dropped to 15~20 DEG C, suction filtration dries to obtain the g of II compound of formula 83.2, yield 89.4%.
Embodiment 11
By the compound of 65 g formulas II, it is dissolved in 510 mL dichloromethane, is cooled to 0~10 DEG C, 47 g are slowly added dropwise into system
Trifluoroacetic acid, insulation tracks to raw material conversion and finished, then sodium hydrate solid is added portionwise, and system pH is adjusted into 9~10, mistake
Filter, concentration, distillation obtains 29.3 g (R) -3- amino butanols, yield 95.8,1H NMR (300MHz, DMSO, ppm): δ
4.48 (3H, s), 3.47 (2H, s), 2.96 (1H, s), 1.47-1.41 (2H, q), 1.02-0.99 (3H,
d)； LCMS (ESI), m/z, 90 [M+H] +.
The present invention is described in detail above, embodiments of the present invention carried out using specific case in the present invention
Illustrate, the explanation of above example is only intended to help and understands the present invention, it is noted that for the technology people of the art
For member, under the premise without departing from the principles of the invention, some improvement can be also carried out to the present invention, these improvement also fall into this hair
In bright scope of the claims.
Claims (9)
- The preparation method of (1. R) -3- amino butanols, it is characterised in that comprise the following steps：S1, with 3-（T-butoxycarbonyl-amino）Butyric acid is raw material, and its chiral resolution is obtained into type I compound；S2, by type I compound sodium borohydride and lewis acid reduction obtain the compound of formula II；S3, the compound of formula II is sloughed into tertbutyloxycarbonyl obtain (R) -3- amino butanols；Reaction equation is as follows：。
- 2. preparation method according to claim 1, it is characterised in that the step S1 chiral resolutions include：By 3-（T-butoxycarbonyl-amino）Butyric acid is dissolved in organic solvent, and under agitating and heating state, resolving agent is added thereto, Insulated and stirred for a period of time, is cooled to 10~15 DEG C, suction filtration, dry carboxylate；Gained carboxylate is added in ethanol, 70~75 DEG C are heated to, after insulation a period of time, 10~15 DEG C are cooled to, suction filtration, Dry, repeat this operation, until gained carboxylate ee values are more than 99%；It is finally that carboxylate is soluble in water, concentrated hydrochloric acid is added, its pH value is adjusted to 1~2, is extracted with ethyl acetate, organic phase is dense It is reduced to no cut and obtains type I compound.
- 3. preparation method according to claim 2, it is characterised in that the organic solvent is methanol, acetone or alcohol.
- 4. preparation method according to claim 2, it is characterised in that the resolving agent be S- phenyl ethylamines, S- naphthalene ethylamines or L- ephedrines.
- 5. preparation method according to claim 4, it is characterised in that add the resolving agent and 3-（Tertbutyloxycarbonyl-ammonia Base）The mol ratio of butyric acid is 0.7~0.9:1.
- 6. preparation method according to claim 1, it is characterised in that in the step S1, by 3-（Tertbutyloxycarbonyl-ammonia Base）Butyric acid is dissolved in organic solvent, is heated with stirring to 40~75 DEG C, and resolving agent is added thereto, and insulated and stirred is for a period of time.
- 7. preparation method according to claim 1, it is characterised in that the step S2 includes：Gained type I compound is dissolved in tetrahydrofuran, 0~20 DEG C of temperature control, adds sodium borohydride, then Louis is added portionwise Acid, is finished, and temperature is risen into 25~50 DEG C, insulation reaction；After completion of the reaction, add water and be quenched, organic phase is concentrated into no cut, be recrystallized to give the compound of formula II.
- 8. preparation method according to claim 7, it is characterised in that the lewis acid is zinc chloride, lithium chloride or iodine Simple substance.
- 9. preparation method according to claim 1, it is characterised in that the step S3 includes：The compound of gained formula II is dissolved in dichloromethane, trifluoroacetic acid is slowly added dropwise into system for 0~10 DEG C of temperature control, be incubated Track to raw material conversion to finish, then sodium hydroxide is added portionwise, system pH is adjusted to 9~10, filtered, concentration, distillation is obtained (R) -3- amino butanols.
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| CN113336655A (en) * | 2020-12-30 | 2021-09-03 | 江西迪赛诺制药有限公司 | Preparation method of (R) -3-aminobutanol |
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Denomination of invention: (R) Preparation of 3-aminobutanol Effective date of registration: 20210420 Granted publication date: 20190702 Pledgee: Bank of Cangzhou Limited by Share Ltd. branch Pledgor: CANGZHOU SENARY CHEMICAL SCIENCE-TEC Co.,Ltd. Registration number: Y2021990000345 |
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