TW503231B - Method for preparing 3-aminot-1,2-propandiol derivatives - Google Patents

Abstract

A method for the preparation of 3-amino-1,2-propandiol derivatives of the formula (I) by reacting a compound of the formula (II) with RNH2, wherein R and R1 have the same meaning as given in the description. The formula (I) derivatives are β-blockers used for treating hypertension.

Description

503231 V. Description of the Invention (/) [Technical Field of the Invention] The present invention relates to a method for producing a 3-amino-propanediol (3-propandiol) derivative. In particular, it relates to a method for synthesizing various kinds of blocker drugs capable of treating hypertension by using the same synthetic osmium. [Technical Background] Many cold-blocking drugs for treating hypertension, such as (s) _Tim〇101, (s) _ Propranolo (S) -Aten〇l〇i and (S) _Met〇pr〇. Both of them have a main structure of 3 amino-1,2-propanediol. Please read the note on the back first

X

NH

S I N

(S) -Timolol

(S) -Propranolol η < Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 503231 A7 B7 V. Description of the invention (>

NH

CH2CONH2 (S) -Metoprolol Printed by NH HOv ^ 1, Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs. General (S) -Atenolol The above-mentioned anti-hypertensive drugs can be used to treat hypertension. Although many synthetic methods have been developed, they all use separate processes to synthesize the required drugs. For example, Weinstock, L M; MulYey, D. M; TuUR · J · Org · Chem · 1976, 41, 3121 · Synthetic (S) -Timoll 101 method has been reported 'but lead tetraacetate (Pb〇) is used in this process. AC4), there will be a problem of waste disposal during mass production. In addition, Carlsen, P. H. J .; Aase, K Acta. Chem. Scand. 1993, 737. There are also reports on the synthetic (S) -Propranoliol method. Since these blockers for the treatment of hypertension all have a 3-amino-1,2-propanediol main structure, if one can develop a manufacturing method based on the fact that these drugs have a partial common structure, as long as the appropriate -CH2CH2OCH3 (Please read the notes on the back before filling this page)

Order --------- ^ 9— This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) A7 A7 ORi Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

V. Description of the invention (multiple raw materials, you can use the same synthetic route to enter the scholarship & continue to synthesize the various drugs mentioned above, it should be quite valuable. [Summary of the invention] 6 spoons of the head of this issue is mainly to provide a Method for synthesizing% amine propylene glycol derivative. Another purpose of this month is to provide a method for synthesizing various kinds of /?-Resistances which can be used to treat hypertension by selecting the proper raw materials. Manufacturing process of sedative drugs. 々_Blocker drugs used to treat hypertension such as (s) _Tim〇101, (s) _ Propranolo Bu (8) -Αίθη〇101 and (^, 纣 叩 ⑺丨 ❹ 丨 and other drugs, they can be covered by the 3-amino-1,2-propanediol derivative of the formula ，,

RNH Η07 (I) where R stands for Cij alkyl, N "CH2CONH2 or Thai paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling out this page}

A7 V. Description of the invention (bovine) ch2ch2och3 Based on the above-mentioned drugs are 3-amino-at derivatives, the inventors have developed the same-path to synthesize the above-mentioned various drugs as long as the appropriate raw materials are selected. Process. The production method of the present invention can be simply expressed by the following reaction formula (a): ii of alcohol synthesis

Tr2N02S

Order H0

(iy-〇Ri Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs h2nr 〇 ·

(II) ORi reaction formula (a) This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) r2so2q HO.

ORi (π ΟcVRi R2S02C1

ch2conh2 or Chuan 3231 A7 B7 V. Description of the invention ({) where R represents Ci · 4 alkyl; preferably, R represents isopropyl and fourth butyl;

Ri stands for

R2 represents Ci-4 alkyl, phenyl, benzyl, or phenyl substituted with Ci-4 alkyl or halogen; preferably, R2 represents methyl, phenyl, or benzyl; with respect to formula (VI ) Synthesis of compounds in Hsu, CY; Lin, YS ·; Uang, BJ,

Tetrahedron: Asymmetry 1990, 1,219 In the literature, glycerol is used as a raw material and a palm auxiliary group is used to perform an asymmetric ketalization reaction to obtain the compound of the above formula (VI). See the following reaction formula ( b).

This paper size applies to China National Standard (CNS) A4 (210 x 297 mm)

~ ΟΪ —OH

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

V. Description of the invention (Here, the compound of formula (VI) is first selected in the present invention. This compound is a chiral glycerol equivalent, and a substitution reaction with a thiol RiX is performed in the presence of a base. The compound of formula can be obtained. The solvent used can be t_BuOH or DME (chmethoxyethane), and the reaction is carried out at reflux temperature. The test used here can be t_BuOK, K2C03 or NaH. After the compound of formula (V) is further hydrolyzed in methanol with acid, the bishydric compound of formula (IV) can be further obtained smoothly. The acid used in the hydrolysis reaction can be, for example, hydrochloric acid. The compound of formula (IV) is then converted into a good leaving group with R2S02Cl (R2 represents (^ -4 alkyl, phenyl, benzyl, or phenyl substituted with d.4 alkyl or halogen). The compound of formula (III) is obtained. The compound of formula (111) is treated with NaH to perform an intramolecular substitution reaction to obtain an epoxy compound of formula (11). The epoxy compound of formula (H) is then reacted with alkylamine RNH2 Reaction, where R stands for C ^ 4 alkyl group can be substituted to obtain the 3-amino propanediol derivative of formula 。. Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs. In addition, the preparation of compounds of formula (v) from compounds of formula (VI) Method: In addition to selecting a compound of formula (VI) to perform a substitution reaction with a haloalkyl R1X, a method such as the compound of formula (V) can be obtained. Alternatively, a compound of formula (VI) can be used to perform a substitution reaction with R2SO2Cl to The compound of the following formula (γι ') is obtained, and the compound of the formula (vr) can be treated with R10H to obtain the compound of the formula (V). See 8 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) ~ ----— Α7 Β7 5. Explanation of the invention (9) The following reaction formula (C),

Prj2N〇2s

〇Ri Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs The definitions of the substituents R2, R1, and X in the reaction formula (c) are as described above. The manufacturing method according to the present invention can be used to synthesize various compounds of Lu blockers used for treating hypertension, such as (S) -Timolol, (s) -Propranol〇l, (S) -Atenolol and (S) -Metoprolol And other drugs. [Specific description of the invention] This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) A7

A7 RNH 5. Description of the invention (5) The present invention relates to a method for producing a 3-amino β1,2-propanediol (3-ammo-1, 2-propandiol) derivative of the following formula:

H0O

Lor! (I) where R stands for Ci-4 alkyl; Ri stands for ^^ (Please read the notes on the back before filling this page)

S I N

CH2CONH2 or

ch2ch2och3 1. Qibu to said i 犲 i members 31 cost savings ^ first appeared. Synthesis of the formula (I) can be a compound of the formula (II) ^ ORi (II) where R1 is defined as described above, and alkyl Amine RNH2 reaction, where R is defined as previously described. The synthesis of the compound of formula (II) is based on the compound of formula (IV). The paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) 503231 A7 B7 V. Description of the invention (jins) Η 丨

Hoy '—OR! (IV) where R1 is defined as described above and reacted with R ^ SC ^ Cl (wherein R2 is defined as described above), and then treated with NaH. How can the synthesis of the compound of formula (IV) be as follows:

(Please read the notes on the back ^^ Fill this page first) mm, printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs and haloalkyl RiX, where Ri is defined as described above, X stands for halogen, and then react with each other. Derived from hydrolysis reaction. With regard to the preparation of the compound of formula (VI), reference may be made to the aforementioned literature published by Hsu, C.Y. et al. For the convenience of further explanation, the following examples will be enumerated for more specific description. [Preferred Embodiments of the Invention] The following embodiments are specific descriptions of the present invention, but they do not limit the scope of the present invention. 11 Using Chinese National Standard (CNS) iT ^ Grid⑽ 297 ~-· i I I I I I-Line Lu · 503231 A7 B7 V. Description of the Invention (Preparation Example

C

NaH

Put 0.267 g of 60% NaH into a 50 ml reaction bottle, wash it twice with 2 ml of anhydrous n-hexanol, drain the solvent with a vacuum pump, and add 25 ml of anhydrous DME (l, 2-dimethoxyethane). Next, 1.99 g of the compound of formula (VI) was added, and then 2.13 g of 3-chloro-4- (N-morpholino) -1,2,5-thiadiazole was added, and heated under reflux. After the reaction was completed, 10 ml of water was added at ice temperature, and extracted with ethyl acetate. After column chromatography analysis, 2.732 g of a white solid compound of the formula (2) was obtained. Melting point: 131.8 ~ 132.6 ° (:, yield 95). % 〇 (Please read the precautions on the back before filling out this page)-· continued ------ «Μ a ·· a ······ < * < μ ··· Μ · ·· Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 12 This paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 503231 A7 B7 V. Description of the invention (") Preparation Example 2

OH & 10

K2C03, DMSO

(Please read the precautions on the back before filling out this page) The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed under the gas-generating 'compound of formula (9) (2.68 g, 5.8 mmol), K2CO (1.77 g , 12.9 millimoles), compound of formula (10) (丨 g, 7.47 millimoles and anhydrous DMSO (25 ml)) were placed in a 50 ml double-necked Yan Ying bottle with a condenser tube and heated to After reacting at 100 ° C for 22 hours, Η20 (20 | liters) was added, and extracted with ether (50 ml x 3), and then washed with saturated brine, dried over frozen sodium sulfate, filtered and concentrated, and ethyl acetate : N-hexane = 1 ·· 5 is the eluent, and column chromatography analysis is performed to obtain the compound of formula (U). After recrystallization using EA as a solvent, a white solid compound of (Π) (2. 00 g, 3.9 millimolar), melting point: 170 ~ 170.6 ° C, yield 68%. 13 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 503231 A7 B7

V. Description of the Invention (/ >) Preparation Example HCl (aq)

A 50 ml reaction bottle of MeOH was charged with 1.53 g of the compound of formula (2), 7 ml of methanol, and 2.8 ml of 2N hydrochloric acid, and heated to 60 ° C. After the reaction was completed, 3 ml of water was added at room temperature, neutralized with NaOH to pH 7 to 8, and extracted with ethyl acetate. After filtration and concentration, 0.652 g of a white solid compound of formula (3) was obtained. Melting point: 122.8 ~ 123.4 ° C, yield 91%. Preparation Example 4 • · 1 n el emmmm n ϋ ϋ *-丨, a 1 «« ϋ I JV—- t 'T (Please read the precautions on the back before filling in this page)

This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 厶 J 丄 A7 V. Description of the invention (/ multiple) In a 25ml starfish x shellfish bottle, add the compound of formula (11) (2.01g , 3 · 8 lmmoles), methanol Θ pen liters) and 2iV HC1 (aq) (4 ml, 8 molars on the condenser tube, then add 埶 to ^ y ...., the main 70 ° C. After 10 hours Then, it was cooled to room temperature, and added 仏 〇 (10mL) 'to adjust the pH to 7-8 with 1M NaOH (aq), and extracted with ethyl acetate (50mL × 3), and the organic layer was washed with saturated brine. , Dried over anhydrous sodium sulfate, filtered and concentrated with ethyl acetate: n-hexane = ι :, as the eluent, and analyzed by column chromatography to obtain a white solid compound of formula (12) (0 · 766 g 3 · 51 mmol), yield 90%, refining point: 111.2 ~ 111.S ° C, yield 95%. Preparation Example 5 · Printed by the Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs

N N 、 S〆 (3)

TsCl

(4) NN, S〆 Put 1.5g of compound of formula (3) into dried woml reaction bottle 15 Table paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----- ---- ^ --------- < Please read the notes on the back before filling in this page) 503231

V. Description of the invention (4)

Then, 20 ml of anhydrous dichloromethane and 2.5 ml of anhydrous pyridine were added, and 1.2 g of toluene sulfonyl chloride (TsCl) was added at -5 to -10 ° C. After the reaction was completed, ml of water was added to the chamber, and the mixture was extracted with dichloromethane. After filtration, concentration, and column chromatography, 1.61 g of a white solid compound of the formula (4) was obtained with a yield of 68%. Preparation Example 6

TsO \ Put 0.22g of 80% NaH into a 50ml reaction bottle which has been dried, and wash it twice with 2 liters of water and n-hexanol, and then wash it once with 2 liters of anhydrous water. After drying, 12 ml of anhydrous THF was added, and 1.47 g of the compound of formula (4) was added at ice temperature. After the reaction was completed, 10 ml of water was added to the chamber and extracted with ethyl acetate. After filtration, concentration and column chromatography analysis, 0.77 g of a white solid compound of formula (5) was obtained with a yield of 90%. 16 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ww I a ·· * MW I MM a ··· · I · mmmmm ϋ ti II 1 ϋ jriJ nn «I ϋ ϋ I · (Hu fills in this page) Printed by the Employees 'Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed 503231, A7 ___ B7 V. Description of the Invention (A) Real Spirit

(S) -Timolol 10 ml reaction flask. 0.15 g of the compound of formula (5), 7.0 ml of tetrabutylamine, and 0.25 ml of water were placed and heated to reflux. After the reaction was completed, 20 ml of ethyl acetate was added, and after filtration and concentration, (19) g of (s) -Tirnoll was obtained as a white solid, 0.19 g in a yield of 97%. Example 2 The steps of Preparation Example 5, Preparation Example 6, and Example 1 were repeated, but the compound of formula (3) was replaced with a compound of formula (12) and t-BuNH2 was replaced with 2-amino propane. You can get (S) -Propranolol 0,.

[Effects of the Invention] The present invention is a novel and efficient method for synthesizing and manufacturing 3-amino-1,2-propanediol derivatives. It is a kind of paper that is synthesized by selecting the appropriate raw materials and using the same 17 paper sizes. Applicable to China National Standard (CNS) A4 (210 X 297 mm) -n III n I ϋ 1 n 1 1 n I nn a 0 * · »> ϋ I ϋ ϋ · 1 -III (Please read the precautions on the back before filling out this page) 503231 A7 B7 V. Description of the invention (4 paths can be used to synthesize a variety of different 10,000-blockers that can be used to treat hypertension For example, (S) -Timolol, (S) -Propranolo, (S) -Atenolol, and (S) _Metoprolol and other drugs. The manufacturing method provided by the present invention has a common synthetic path, so the present invention is in production When the above medicines are used, the equipment can be shared, so that the present invention has more advantageous advantages in production. Please read the note of S)

Order 4 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

8 1X This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Claims (1)

503231 A8 B8 C8 D8 VI. Scope of patent application announcement RNH H0 (I) 1. A method for producing a 3-amino-1,2-propandiol derivative of the formula (I), OR! Wherein: R represents C! _4 alkyl (Please read the notes on the back before filling this page) CH2CH2OCH3 CH2CONH2 or The ORi printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs includes the compound T (II) of the following formula (II), wherein R1 is defined as described above, and reacts with alkylamine RNH2, where R represents Ci-4 alkyl, where the The compound of formula (II) is the compound of formula (IV). The paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm). VI. Application scope ABQS HO ORi (IV) where Ri is defined as previously described, and reacts with R2S02Ci, where r2 represents 匸]-, a radical, an acyl group, a benzyl group, or a phenyl group substituted with a Cl_4 alkyl group or a halogen compound, and then NaH treatment. 2. The manufacturing method according to item 1 of the application, wherein R represents isopropyl or fourth butyl. 3. If the manufacturing method of item 1 of the patent application scope, where Rl represents 4 ------------ (Please read the precautions on the back before filling this page) N 〇 4. The manufacturing method according to item 1 of the scope of patent application, wherein the derivative of formula (I) is (S) -Timolol as follows. ---: 丨 Order ----- Line Voice Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy X HO NH N XT 0 20 This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) AS B8 C8 D8 VI. Application for patent scope 5 · If the manufacturing method of the first scope of patent application, the compound of formula (IV) 0H and fluorene alkyl R] [X, where R is defined as in item 1 of the scope of patent application, and X represents halogen, which is obtained after a phase reaction followed by a hydrolysis reaction. For example, the manufacturing method of the first scope of the patent application, wherein the compound of formula (IV) is a substitution reaction of the aforementioned compound of the formula (VI) and r2s〇2C1, wherein the definition of rule 2 is as described in the first scope of the patent application. After treatment with RiOH, the definition is as in item 1 of the scope of patent application, and then obtained by hydrolysis reaction. ------------ 丨 ^^ -------, 丨 Order 丨 · -------- line lip. (Please read the phonetic on the back? Matters before filling in this Page} Printed Standard for Employee Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (c ^ T4 specification (210_ 21 X 297 mm)