CN106966912B - (R) preparation method of -3- amino butanol - Google Patents
(R) preparation method of -3- amino butanol Download PDFInfo
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- CN106966912B CN106966912B CN201710213571.7A CN201710213571A CN106966912B CN 106966912 B CN106966912 B CN 106966912B CN 201710213571 A CN201710213571 A CN 201710213571A CN 106966912 B CN106966912 B CN 106966912B
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention relates to pharmaceutical intermediate synthesis technical fields, specifically disclose a kind of preparation method of Du Lutewei intermediate (R) -3- amino butanol, are using 3-(Boc- amino) butyric acid as starting material, obtains type I compound by chiral resolution；It restores to obtain II compound of formula using sodium borohydride and lewis acid；Last amino is deprotected to obtain (R) -3- amino butanol.Raw material used in the method for the present invention is cheap and easy to get, and reaction condition is mild, and safety is reliable, and technology stability is good, high income, and optical purity is high, environmentally protective, is suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical intermediate synthesis technical fields.
Background technique
Du Lutewei, also known as De Luogewei, English name: Dolutegravir, trade name: Tivicay is by Britain's system
Medicine giant GlaxoSmithKline PLC (GSK) and a kind of anti-AIDS that Japanese Shionogi company (Shionogi) is developed cooperatively are new
Medicine.
(R) -3- amino butanol is the important intermediate for synthesizing Du Lutewei, and structural formula is as follows:
。
The prior art preparation intermediate there are the problem of be mainly reflected in following several points: reaction route is longer, overall to receive
Rate is low, and technological operation is harsher, needs to use toxic articles and explosive sensitive materials.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation methods of (R) -3- amino butanol, have reaction route
The advantages that short, mild condition, safe and reliable, technology stability are well, low energy consumption, high income, obtained (R) -3- amino butanol
Optical purity is high, and the method for the present invention is environmentally protective, is suitable for industrialized production.
In order to solve the above technical problems, the technical solution used in the present invention is: the preparation method of (R) -3- amino butanol,
The following steps are included:
S1, using 3-(t-butoxycarbonyl-amino) its chiral resolution as raw material, obtains type I compound by butyric acid；
S2, type I compound sodium borohydride and lewis acid are restored to obtain II compound of formula；
S3, it II compound of formula is sloughed into tertbutyloxycarbonyl obtains (R) -3- amino butanol；
Reaction equation is as follows:
。
Further, the step S1 chiral resolution includes:
By 3-(t-butoxycarbonyl-amino) butyric acid is dissolved in organic solvent, under agitating and heating state, preferred control temperature 40
~75 DEG C, it is added resolving agent thereto, insulated and stirred for a period of time, is cooled to 10~15 DEG C, filters, dry carboxylate；
Gained carboxylate is added in ethyl alcohol, is heated to 70~75 DEG C, after keeping the temperature a period of time, is cooled to 10~15 DEG C,
It filters, is dry, repeating this operation, until gained carboxylate ee value is greater than 99%；
It is finally that carboxylate is soluble in water, concentrated hydrochloric acid is added, adjusts its pH value to 1~2, is extracted with ethyl acetate, it is organic
It is mutually concentrated into no fraction and obtains type I compound.
Wherein, the organic solvent is methanol, acetone or alcohol；The resolving agent is S- phenyl ethylamine, S- naphthalene ethylamine or L-
Ephedrine is preferably added to the resolving agent and 3-(t-butoxycarbonyl-amino) molar 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, sodium borohydride is added, then road is added portionwise
Lewis acid finishes, and temperature is risen to 25~50 DEG C, insulation reaction；
After completion of the reaction, water quenching is added to go out, organic phase is concentrated into no fraction, is recrystallized to give II compound of formula.
Optionally, the lewis acid is zinc chloride, lithium chloride or elemental iodine.
Further, the step S3 includes:
It is dissolved in II compound of gained formula in methylene chloride, 0~10 DEG C of temperature control, trifluoroacetic acid is slowly added dropwise into system,
Heat preservation tracks to raw material conversion and finishes, then sodium hydroxide is added portionwise, and system pH is adjusted to 9~10, is filtered, and concentration is distilled
To (R) -3- amino butanol.
The beneficial effects of adopting the technical scheme are that the method for the present invention has, reaction route is short, condition temperature
With the advantages that safe and reliable, technology stability is good, low energy consumption, high income, obtained (R) -3- amino butanol optical purity
It is high.The method of the present invention is environmentally protective, is suitable for industrialized production, particularly suitable for the preparation of Du Lutewei intermediate.
Specific embodiment
The present invention provides a kind of preparation method of Du Lutewei intermediate (R) -3- amino butanol, is with 3-(Boc- amino)
Butyric acid is starting material, obtains type I compound by chiral resolution；
It restores to obtain II compound of formula using sodium borohydride and lewis acid；
Last amino is deprotected to obtain (R) -3- amino butanol.
It illustrates below and the method for the present invention is described in further detail.
Embodiment 1
By 20.3 g 3-(Boc- amino) butyric acid is dissolved in 40.6 mL methanol, 40~50 DEG C are heated with stirring to, in the temperature
10.2 mL methanol solutions of 9.1 g S- phenyl ethylamines are slowly added dropwise under degree, drop finishes, 20~30 min of insulated and stirred, Slow cooling
To 10~15 DEG C, filter, dry 14 g of carboxylate；Then 14 g carboxylates are added in 28 mL ethyl alcohol, are heated to 70~75
DEG C, 15~20 min are kept the temperature, are slowly dropped to 10~15 DEG C, are filtered, dry 13 g of carboxylate repeats this operation 2 times, obtains carboxylic
12.2 g of hydrochlorate, ee value 99.7%；Finally 12.2 g carboxylates are added in 36 mL water, pH is adjusted to 1~2 with concentrated hydrochloric acid, is added
Enter 30 mL ethyl acetate to be extracted twice, merges organic phase and be concentrated into no fraction, obtain 7.6 g of type I compound.
Embodiment 2
By 30 g 3-(Boc- amino) butyric acid is dissolved in 60 mL ethyl alcohol, 70~75 DEG C are heated with stirring to, at such a temperature
15 mL ethanol solutions of 14 g S- phenyl ethylamines are slowly added dropwise, drop finishes, and 20~30 min of insulated and stirred slowly cools to 10~15
DEG C, it filters, dry 21.6 g of carboxylate；Then 21.6 g carboxylates are added in 43.2 mL ethyl alcohol, are heated to 70~75
DEG C, 15~20 min are kept the temperature, are slowly dropped to 10~15 DEG C, are filtered, dry 20 g of carboxylate repeats this operation 2 times, obtains carboxylic
18.8 g of hydrochlorate, 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, is added
Enter 50 mL ethyl acetate to be extracted twice, merges organic phase and be concentrated into no fraction, obtain 11.7 g of type I compound.
Embodiment 3
By 50 g 3-(Boc- amino) butyric acid is dissolved in 150 mL acetone, 40~50 DEG C are heated with stirring to, at such a temperature
It is slowly added dropwise 50 mL acetone solns of 20.9 g S- phenyl ethylamines, drop finishes, 20~30 min of insulated and stirred, slowly cool to 10~
It 15 DEG C, filters, dry 36 g of carboxylate；Then 36 g carboxylates are added in 72 mL ethyl alcohol, are heated to 70~75 DEG C, protected
15~20 min of temperature, are slowly dropped to 10~15 DEG C, filter, and dry 33.8 g of carboxylate repeats this operation 2 times, obtains carboxylic acid
32 g of salt, 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 are added
Ethyl acetate is extracted twice, and is merged organic phase and is concentrated into no fraction, obtains 19.6 g of type I compound.
Embodiment 4
By 50 g 3-(Boc- amino) butyric acid is dissolved in 150 mL acetone, 40~50 DEG C are heated with stirring to, at such a temperature
It is slowly added dropwise 50 mL acetone solns of 23.9 g S- phenyl ethylamines, drop finishes, 20~30 min of insulated and stirred, slowly cool to 10~
It 15 DEG C, filters, dry 37.2 g of carboxylate；Then 37.2 g carboxylates are added in 75 mL ethyl alcohol, are heated to 70~75
DEG C, 15~20 min are kept the temperature, are slowly dropped to 10~15 DEG C, are filtered, dry 34.7 g of carboxylate repeats this operation 2 times, obtains
33.3 g of carboxylate, 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,
85 mL ethyl acetate are added to be extracted twice, merges organic phase and is concentrated into no fraction, obtain 20.5 g of type I compound.
Embodiment 5
By 50 g 3-(Boc- amino) butyric acid is dissolved in 150 mL acetone, 40~50 DEG C are heated with stirring to, at such a temperature
It is slowly added dropwise 50 mL acetone solns of 26.9 g S- phenyl ethylamines, drop finishes, 20~30 min of insulated and stirred, slowly cool to 10~
It 15 DEG C, filters, dry 38 g of carboxylate；Then 38 g carboxylates are added in 75 mL ethyl alcohol, are heated to 70~75 DEG C, protected
15~20 min of temperature, are slowly dropped to 10~15 DEG C, filter, and dry 35.2 g of carboxylate repeats this operation 2 times, obtains carboxylic acid
33.8 g of salt, 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, is added
85 mL ethyl acetate are extracted twice, and are merged organic phase and are concentrated into no fraction, obtain 20.8 g of type I compound.
Embodiment 6
By 71 g 3-(Boc- amino) butyric acid is dissolved in 142 mL methanol, 40~50 DEG C are heated with stirring to, at such a temperature
35.5 mL methanol solutions of 47.8 g S- naphthalene ethylamines are slowly added dropwise, drop finishes, and 20~30 min of insulated and stirred slowly cools to 10
It~15 DEG C, filters, dry 59 g of carboxylate；Then 59 g carboxylates are added in 148 mL ethyl alcohol, are heated to 70~75 DEG C,
15~20 min are kept the temperature, are slowly dropped to 10~15 DEG C, are filtered, dry 56.6 g of carboxylate repeats this operation 2 times, obtains carboxylic
52 g of hydrochlorate, ee value 99.8%；Finally 52 g carboxylates are added in 156 mL water, pH is adjusted to 1~2 with concentrated hydrochloric acid, is added
130 mL ethyl acetate are extracted twice, and are merged organic phase and are concentrated into no fraction, obtain 27.9 g of type I compound.
Embodiment 7
By 90 g 3-(Boc- amino) butyric acid is dissolved in 225 mL ethyl alcohol, 70~75 DEG C are heated with stirring to, at such a temperature
It is slowly added dropwise 60 mL ethanol solutions of 58.5 g L- ephedrines, drop finishes, 20~30 min of insulated and stirred, slowly cool to 10~
It 15 DEG C, filters, dry 78.5 g of carboxylate.Then 78.5 g carboxylates are added in 200 mL ethyl alcohol, are heated to 70~75
DEG C, 15~20 min are kept the temperature, are slowly dropped to 10~15 DEG C, are filtered, dry 75.3 g of carboxylate repeats this operation 2 times, obtains
69.2 g of carboxylate, 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,
150 mL ethyl acetate are added to be extracted twice, merges organic phase and is concentrated into no fraction, obtain 37.1 g of type I compound.
Embodiment 8
115 g type I compounds are dissolved in 460 mL tetrahydrofurans, ice bath is cooled to 0~10 DEG C, then is added portionwise 23.7
G sodium borohydride, 0~10 DEG C of temperature control, then 230 mL tetrahydrofuran solutions of 165.4 g iodines are slowly added dropwise into system, drop
Finish, be gradually heated to 25~30 DEG C, liquid phase tracks to raw material conversion and finishes, and 60 mL water quenching reactions are added dropwise, are concentrated under reduced pressure into nothing
500 mL methanol are added in fraction, after being warming up to 55~60 DEG C of dissolved clarifications, keep the temperature 0.5 h, 1050 mL water are added dropwise at such a temperature, drip
Finish, 1 h of insulated and stirred, then be slowly dropped to 15~20 DEG C, filters, dry to obtain II compound of formula, 97.4 g, 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 is added portionwise 20.2
G sodium borohydride, 0~10 DEG C of temperature control, then 113.9 g zinc chloride are added portionwise into system, drop finishes, and is gradually heated to 25~30
DEG C, liquid phase tracks to raw material conversion and finishes, and 45 mL saturated ammonium chloride quenching reactions are added dropwise, are concentrated under reduced pressure into no fraction, is added
350 mL1 mol/L aqueous hydrochloric acid solutions and the extraction of 510 mL ethyl acetate, water phase use 170 mL ethyl acetate to extract again, merge
350 mL methanol are added in organic phase, concentration, after being warming up to 55~60 DEG C of dissolved clarifications, keep the temperature 0.5 h, 880 are added dropwise at such a temperature
ML water, drop finish, 1 h of insulated and stirred, then are slowly dropped to 15~20 DEG C, filter, dry to obtain II compound of formula, 70.2 g, 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 is added portionwise 24.6
G sodium borohydride, 0~10 DEG C of temperature control, then 46 g lithium chlorides are added portionwise into system, drop finishes, and is gradually heated to 25~30 DEG C, liquid
It mutually tracks to raw material conversion to finish, 55 mL saturated ammonium chloride quenching reactions is added dropwise, are concentrated under reduced pressure into no fraction, 400 mL1 are added
Mol/L aqueous hydrochloric acid solution and the extraction of 600 mL ethyl acetate, water phase use 200 mL ethyl acetate to extract again, merge organic phase, dense
350 mL methanol are added in contracting, after being warming up to 55~60 DEG C of dissolved clarifications, keep the temperature 0.5 h, and 950 mL water are added dropwise at such a temperature, and drop finishes,
1 h of insulated and stirred, then 15~20 DEG C are slowly dropped to, it filters, dries to obtain II compound of formula, 83.2 g, yield 89.4%.
Embodiment 11
By 65 g formula, II compound, it is dissolved in 510 mL methylene chloride, is cooled to 0~10 DEG C, is slowly added dropwise into system
47 g trifluoroacetic acids, heat preservation tracks to raw material conversion and finishes, then sodium hydrate solid is added portionwise, and system pH is adjusted to 9~10,
Filtering, concentration distill and obtain 29.3 g (R) -3- amino butanol, yield 95.8, and 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 are carried out using specific case in the present invention
It illustrates, the present invention that the above embodiments are only used to help understand, it is noted that for the technology people of the art
For member, without departing from the principle of the present invention, can also several improvement be carried out to the present invention, these improvement also fall into this hair
In bright scope of protection of the claims.
Claims (7)
- The preparation method of (1. R) -3- amino butanol, which comprises the following steps:S1, using 3- (t-butoxycarbonyl-amino) butyric acid as raw material, its chiral resolution is obtained into type I compound；S2, type I compound sodium borohydride and lewis acid are restored to obtain II compound of formula；S3, it II compound of formula is sloughed into tertbutyloxycarbonyl obtains (R) -3- amino butanol；Reaction equation is as follows:The step S1 chiral resolution includes:3- (t-butoxycarbonyl-amino) butyric acid is dissolved in organic solvent, 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, filters, dry carboxylate；The resolving agent is S- phenyl ethylamine, S- naphthalene Ethamine or L- ephedrine；Gained carboxylate is added in ethyl alcohol, is heated to 70~75 DEG C, after keeping the temperature a period of time, is cooled to 10~15 DEG C, filter, It is dry, this operation is repeated, until gained carboxylate ee value is greater than 99%；It is finally that carboxylate is soluble in water, concentrated hydrochloric acid is added, adjusts its pH value to 1~2, is extracted with ethyl acetate, organic phase is dense It is reduced to no fraction and obtains type I compound.
- 2. preparation method according to claim 1, which is characterized in that the organic solvent is methanol, acetone or alcohol.
- 3. preparation method according to claim 1, which is characterized in that the resolving agent and 3- (tertbutyloxycarbonyl-ammonia is added Base) butyric acid molar ratio be 0.7~0.9:1.
- 4. preparation method according to claim 1, which is characterized 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, resolving agent is added thereto, and insulated and stirred is for a period of time.
- 5. preparation method according to claim 1, which is characterized in that the step S2 includes:Gained type I compound is dissolved in tetrahydrofuran, 0~20 DEG C of temperature control, sodium borohydride is added, then Louis is added portionwise Acid finishes, and temperature is risen to 25~50 DEG C, insulation reaction；After completion of the reaction, water quenching is added to go out, organic phase is concentrated into no fraction, is recrystallized to give II compound of formula.
- 6. preparation method according to claim 5, which is characterized in that the lewis acid is zinc chloride, lithium chloride or iodine Simple substance.
- 7. preparation method according to claim 1, which is characterized in that the step S3 includes:It is dissolved in II compound of gained formula in methylene chloride, 0~10 DEG C of temperature control, trifluoroacetic acid is slowly added dropwise into system, keeps the temperature It tracks to raw material conversion to finish, then sodium hydroxide is added portionwise, system pH is adjusted to 9~10, is filtered, concentration, distillation obtains (R) -3- amino butanol.
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