KR20100010793A - A novel method for the preparation of hexahydrocannabinol derivatives - Google Patents

Abstract

PURPOSE: A method for preparing hexahydrocannabinol derivative which is a kind of cannabinoid is provided to ensure high yield of target compound through one-step reaction. CONSTITUTION: A hexahydrocannabinol of general formula II is prepared by reacting aldehyde having unsaturated bond with a compound of general formula I in the presence of non reaction organic solvent under the presence of catalyst. In general formula I, R1 is hydrogen, OH, OCH3, OEt, ether group, alkenyl group; R2 is hydrogen, carbonyl, ester group or alkenyl group; R3 is alkyl group such as hydrogen, methyl, ethyl, and pentanyl or alkenyl group; and R4 is hydrogen, alkyl or alkenyl group. The aldehyde having unsaturated bond citral, citronellal, citronelly oxyacetalde hyde, cyclamen aldehyde, hydroxycitronellal, lilial or bourgeonal.

Description

A new method for preparing hexahydrocannabiol derivatives {A NOVEL METHOD FOR THE PREPARATION OF HEXAHYDROCANNABINOL DERIVATIVES}

The present invention relates to a method for preparing a hexahydrocannabiol derivative represented by [Formula I] by reacting a compound represented by [Formula II] with an aldehyde in the presence of a catalyst.

Cannabinoids including hexahydrocannabiol of the present invention are compounds present in cannabis savita L (cannabis, Cannabis sativa L) in nature, and cannabis sativa L. has 420 different components. Of these, 66 compounds belong to the class of cannabinoids, and naturally classified cannabinoids are shown in Table 1 below.

Among these cannabis sativa L. components, they exhibit hallucinations, and the main components of cannabinoids are tetrahydrocannabinol and cannabidiol, which initially have pleasure, gladness and hallucination in the central nervous system, cerebrum and spinal cord. It causes excitement, and when it passes, it causes phenomena such as physical paralysis, which is thought to be due to blocking of the external neurotransmitter system.

The important cannabinoids are Δ ⁹ -THC (delta-9-tetrahydrocannabinol) and Δ ⁸ -THC (delta-8-tetrahydrocannabinol). Recently, synthetic Δ ⁹ -THC derivatives have been used under the trade names Dronabinol, Marinol, and Cesame, which are antiemetic drugs.

Δ ⁸ -THC (delta-8-tetrahydrocannabinol) △ ⁹ -THC (delta-9-tetrahydrocannabinol)

Among the analogs of cannabiol, hexahydrocannabiol (HHC) has two enantiomers of (-)-HHC and (+)-HHC as follows, and (-)-HHC is similar to Δ ⁸ -THC. It shows activity and has attracted much attention recently.

     (-)-HHC (+)-HHC

Synthesis of the hexahydrocannabiol (-)-HHC and (+)-HHC compounds is carried out by Tietze using 1,3-cyclohexanedione as a starting material, and the Knoevenagel / Diels-Alder reaction and oxidation to benzene ring. In three stages (Tietze, LF; von Kiedrowski, G., Berger, B. Angew. Chem, Int. Ed. 1982, 21, 221). In addition, Cornia uses five steps of condensation of olivetol with (R)-(+) or (S)-(-)-citronellal using diethylaluminum chloride as a catalyst (Casiraghi, G .; Cornia, M .; Casnati, G .; Fava, GG; Ferrare, M. J. Chem. Soc., Chem. Commun. 1986, 271).

However, the known synthesis methods for such hexahydrocannabiol show various problems in mass production due to various stages of reaction, difficult reaction conditions, and low yield. Above all, it is difficult to approach the preparation of hexahydrocannabiol derivatives through known synthetic methods.

The present invention is to provide a method for producing the hexahydrocannabiol and its derivatives in a high yield through a one-step reaction in order to solve the problems of the prior art as described above.

The present invention relates to a method for producing a hexahydrocannabiol derivative represented by the following [formula I].

[Formula I]

In Formula [I], R ₁ is hydrogen, OH, OCH ₃ , OEt, ether group, algenyl group, R ₂ is hydrogen, carbonyl, ester group, and alkenyl group, R ₃ is hydrogen, methyl, Alkyl groups and alkyl groups such as ethyl, pentanyl and R ₄ refer to hydrogen, alkyl and alkenyl groups. Or A in the general formula [I] means naphthyl, quinolyl, isoquinolyl, quinolizylyl, quinolsalinyl and dibenzofuryl ring.

The cannabinoid analogs prepared by the present invention may have a chiral center and exist as racemates and diastereomers at the 6a, 10a positions of [Formula I]. Due to the physicochemical differences of these components, diastereomers can be separated into their racemic variants in a known manner.

Racemates can be prepared by known methods, for example by microorganisms, or by reaction with optically active acids or bases that form salts with racemic compounds, by separation of diastereomers by fractional crystallization and by suitable preparations. The glass of the enantiomers can be separated by recrystallization in an optically active solvent. Advantageously, more active optical isomers are separated. However, according to the invention, it is also possible to obtain pure enantiomers by asymmetric synthesis, which selects the aldehyde reacting with the above [formula I].

The present invention provides a method for preparing the hexahydrocannabiol derivative of the general formula (I) by reacting a compound of the general formula (II) with a Diels-Alder ring addition reaction with an aldehyde in the presence of a catalyst of ethylenediamine diacetate. .

[Formula II]

In Formula [II], R ₅ is a hydrocarbon having a hydrogen, a hydroxy group, a carbonyl group, or an ester group, or in [Formula II], R ₅ is a naphthyl, quinolyl, isoquinolyl, quinoli with a B ring. A group selected from genyl, quinolsalinyl and dibenzofuryl.

Aldehydes used to produce hexahydrocannabiol derivatives by reacting with the compound of [Formula II] are unsaturated having 8 to 18 carbon atoms that can act as dienophile and having double bonds between carbons. Aldehydes such as citral, citronellal, citronellyl oxyacetalde hyde, cyclamen aldehydes, hydroxycitronellal, lilial and It is selected from bourgeonal.

The following citral and citronellal analogues of the compounds correspond to double bonds in the molecule, and when reacted with the compound of [Formula II], may be cyclohexanated at one or both positions, each of which the optical isomer is exist.

           Citral Citronellal

The preparation method according to the present invention takes place in a non-reactive organic solvent, and non-reactive organic solvents commonly used include dichloromethane, chloroform, 1-2-dibromoethane, 1-bromo-2-chloroethane, 1, Halogenated hydrocarbons such as 1-dibromoethane, 2-chlorofuropane, 1-iodofuropane, chlorobenzene, bromobenzene and 1,2-dichlorobenzene: aromatic solvents such as benzene, toluene, xylene: diethyl Ethers such as ethers, dimethyl ethers, dimethyl ethers and diisofurophyl ethers. Preferred non-reactive organic solvents are halogenated hydrocarbons and aromatic solvents.

Hereinafter, the present invention will be described in more detail.

The present invention provides a method for preparing the compound of [Formula I] by reacting an aldehyde having an unsaturated bond with an aldehyde having an unsaturated bond, an Aldol reaction, and a Diels-Alder cycloaddition reaction. .

Although the following reaction scheme is demonstrated to the manufacturing method of the compound represented by any one of said [formula I] which concerns on this invention as an example, the following description does not limit the scope of the present invention.

Methyl 2,4-dihydroxybenzoate (1 mmol) was reacted with (R)-(+)-citronellal (2 mmol). The reaction scheme at this time is as follows [Scheme 1].

Scheme 1

                         Product a product b

In this case, a mixed catalyst of indium (III) chloride, ytterbium (III) triflate, pyridine, ethylenediamine diacetate and ethylenediamine diacetate / triethylamine was used as a catalyst, and aceto was used as a solvent. Using nitrile or xylene, respectively, under the following conditions, the yields of the products a and b were measured, and the results are shown in the following [Table 2].

Used catalyst Catalyst usage Reaction condition yield Product (a) Product (b) InCl3 10 mol% Acetonitrile. Reflux, 12 hours 0 0 Yb (OTf) 3 10 mol% Acetonitrile. Reflux, 12 hours 8 3 pyridine Overdose 140C, 24 hours 0 0 EDDA (ethylenediamine diacetate) 20 mol% Xylene, reflux, 24 hours 30 40 Triethylamine (TEA) 2 mL Xylene, reflux, 24 hours 10 30 EDDA and TEA Mixed Catalyst 20 mol% + 2 mL Xylene, reflux, 24 hours 0 85

Spectroscopic data of the product a and b produced at this time is as follows.

Product a:

¹ H NMR (CDCl ₃ , 300 MHz) δ 11.35 (1H, s), 7.70-7.50 (2H, m), 6.43 (1H, d, J = 16.6 Hz), 6.07 (1H, dd, J = 16.6, 7.8 Hz), 5.10 (1H, t, J = 7.1 Hz), 3.89 (3H, s), 2.40-2.31 (1H, m), 2.06-1.99 (2H, m), 1.62 (3H, s), 1.58 ( 3H, s), 1.45-1.37 (2H, m), 1.10 (3H, d, J = 6.7 Hz);

IR (neat) 3406, 2955, 1667, 1618, 1499, 1439, 1341, 1273, 1204, 1150, 984, 791 cm ^-1 .

Product b:

[α] _D ²⁰ -127.7 ^o (c 0.30, CHCl ₃ );

¹ H NMR (CDCl ₃ , 300 MHz) δ 11.56 (1H, s), 7.59 (1H, d, J = 8.9 Hz), 6.29 (1H, d, J = 8.9 Hz), 3.86 (3H, s), 3.18 (1H, br d, J = 12.8 Hz), 2.52-2.44 (1H, m), 1.86-1.80 (2H, m), 1.67-1.52 (3H, m), 1.46-1.40 (1H, m), 1.37 ( 3H, s), 1.14-1.10 (1H, m), 1.05 (3H, s), 0.93 (3H, d, J = 6.6 Hz);

¹³ C NMR (CDCl ₃ , 75 MHz) δ 171.2, 162.5, 160.2, 128.6, 112.9, 109.6, 104.3, 78.3, 51.8, 48.8, 38.2, 35.4, 35.2, 32.7, 27.9, 27.5, 22.5, 19.1;

IR (neat) 2949, 1663, 1622, 1582, 1489, 1439, 1339, 1260, 1209, 1138, 1086, 1069, 1003, 914, 883 cm ^-1 .

As shown in Table 2, when the mixed catalyst of EDDA / TEA was used, only the product b in which the aldol reaction and the cyclization reaction of [Scheme 1] occurred was produced in 85% yield. It was found that methyl 2,4-dihydroxybenzoate (1 mmol) was reacted with (R)-(+)-citronellal (2 mmol) via Didol-Alder ring addition to o-quinone metade (o). -quinone methide) can be produced and explained by the synthesis of only one isomer due to the strong exo selectivity of the o-quinone metade in the Diels-Alder reaction (see Scheme 2 below).

Scheme 2

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited thereto.

Example  One.

(-)-3,6,6,9- Tetramethyl -6a, 7,8,9,10,10a- hexahydro -6H- benzo [c] chromen-1- ol  Preparation of (1a) and (+)-3,6,6,9-Tetramethyl-6a, 7,8,9,10,10a-hexahydro-6H-benzo [c] chromen-1-ol (1b)

5-methyl-substituted resorcinol (124 mg, 1 mmol), that is, orcinol, was used as the [Formula II] compound, and aldehyde (R)-(+)-citronellal (308 mg, 2 mmol) or (S)- (-)-citronellal (308 mg, 2 mmol) was used, and the catalyst was reacted under reflux conditions of xylene for 24 hours using EDDA (36 mg, 0.2 mmol) / TEA (2 mL) mixed catalyst as the following [Table 3] and Similarly, Compound 1a (177 mg, 68%) and Compound 1b (182 mg, 70%) were obtained as products.

Formula II Compound Aldehyde Reaction time product yield

   (R)-(+)-citronellal    24 hours

   68

   (S)-(-)-citronellal    24 hours

   70

Spectroscopic data of the compounds 1a and 1b are as follows.

Compound 1a:

[α] _D ²⁰ -90.9 ^o (c 0.18, CHCl ₃ );

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.26 (1H, s), 6.08 (1H, s), 5.67 (1H, s), 3.09 (1H, br d, J = 12.6 Hz), 2.51-2.43 (1H , m), 2.16 (3H, s), 1.86-1.83 (2H, m), 1.73-1.59 (3H, m), 1.49-1.42 (1H, m), 1.38 (3H, s), 1.14-1.10 (1H m), 1.07 (3H, s), 0.94 (3H, d, J = 6.6 Hz);

¹³ C NMR (CDCl ₃ , 75 MHz) δ 154.9, 154.7, 137.2, 110.5, 110.2, 108.5, 77.1, 49.1, 38.8, 35.4, 35.3, 32.7, 27.9, 27.4, 22.5, 20.9, 18.7;

IR (neat) 3387, 2922, 1624, 1580, 1510, 1454, 1332, 1267, 1188, 1138, 1115, 1086, 1057, 1001, 821, 740 cm ^-1 .

Compound 1b:

[α] _D ²⁰ +94.5 ^o (c 0.20, CHCl ₃ );

Example  2.

(-)- Hexahydrocannabinol  (2a) and (+)- Hexahydrocannabinol  Preparation of (2b)

Olivetol (180 mg, 1.0 mmol) was used as the [Formula II] compound, and aldehyde (R)-(+)-citronellal (308 mg, 2 mmol) or (S)-(-)-citronellal (308 mg) was used. , 2mmol), and EDDA (36mg, 0.2mmol) / TEA (2mL) mixed catalyst as a catalyst, reacted under reflux conditions for 24 hours to reflux the compound 2a (228 mg) as a product as shown in Table 4 below. , 72%) and compound 2b (231 mg, 73%) were obtained, respectively.

Formula II Compound Aldehyde Reaction time product yield

   (R)-(+)-citronellal    24 hours

   72

   (S)-(-)-citronellal    24 hours

   73

Spectroscopic data about the compound 2a, 2b is as follows.

Compound 2a:

[α] _D ²⁰ -85.4 ^o (c 0.30, CHCl ₃ );

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.23 (1H, s), 6.06 (1H, s), 4.82 (1H, s), 3.02 (1H, br d, J = 12.6 Hz), 2.47-2.38 (3H , m), 1.85-1.81 (2H, m), 1.60-1.51 (5H, m), 1.35 (3H, s), 1.30--1.25 (4H, m), 1.08-1.05 (1H, m), 1.05 ( 3H, s), 0.89 (3H, d, J = 6.6 Hz), 0.86-0.84 (3H, m), 0.79-0.72 (1H, m);

¹³ C NMR (CDCl ₃ , 75 MHz) δ 154.9, 154.7, 110.3, 109.9, 107.6, 77.0, 49.1, 38.9, 35.5, 35.4, 32.8, 31.5, 30.6, 28.0, 27.7, 22.6, 22.5, 19.0, 14.0;

IR (neat) 3406, 2926, 2865, 1624, 1578, 1426, 1358, 1138, 1038, 828 cm ^-1 .

Compound 2b:

[α] _D ²⁰ +86.9 ^o (c 0.10, CHCl ₃ );

Example  3.

(-)-1- (1- Hydroxy -6,6,9- trimethyl -6a, 7,8,9,10,10a- hexahydro -6H-benzo [c] chromen-2-yl) ethanone (3a) and (+)-1- (1- Hydroxy -6,6,9- trimethyl Preparation of 6a, 7,8,9,10,10a-hexahydro-6H-benzo [c] chromen-2-yl) ethanone (3b)

2,4-dihydroxyacetophenone (152 mg, 1 mmol) and (R)-(+)-citronellal (308 mg, 2 mmol) or (S)-(-)-citronellal as the [General Formula II] compound (308 mg, 2 mmol) was used, and EDDA (36 mg, 0.2 mmol) / TEA (2 mL) mixed catalyst was used as a catalyst. The reaction was carried out under reflux conditions for 16 hours. (216 mg, 75%) and Compound 3b (219 mg, 76%) were obtained, respectively.

Formula II Compound Aldehyde Reaction time product yield

(R)-(+)-citronellal 16

75

(S)-(-)-citronellal 16

76

Spectroscopic data of the compound 3a, 3b is as follows.

Compound 3a:

[α] _D ²⁰ -118.6 ^o (c 0.25, CHCl ₃ );

¹ H NMR (CDCl ₃ , 300 MHz) δ 13.5 (1H, s), 7.43 (1H, d, J = 8.9 Hz), 6.27 (1H, d, J = 8.9 Hz), 3.17 (1H, br d, J = 12.6 Hz), 2.57-2.48 (1H, m), 2.49 (3H, s), 1.85-1.78 (2H, m), 1.65-1.57 (3H, m), 1.49-1.42 (1H, m), 1.37 (3H, s), 1.14-1.04 (1H, m), 1.04 (3H, s), 0.91 (3H, d, J = 6.6 Hz);

¹³ C NMR (CDCl ₃ , 75 MHz) δ 202.6, 164.2, 160.9, 129.8, 112.9, 112.8, 109.4, 78.6, 48.6, 38.1, 35.4, 34.9, 32.6, 27.8, 27.4, 26.1, 22.4, 19.1;

IR (neat) 2922, 1620, 1487, 1414, 1372, 1331, 1260, 1211, 1144, 1067, 912, 882, 847, 802 cm ^-1 .

Compound 3b:

[α] _D ²⁰ +123.4 ^o (c 0.30, CHCl ₃ );

Example  4.

(+)-1- Hydroxy -6,6,9- trimethyl -6a, 7,8,9,10,10a- hexahydro -6H- benzo [c] chromene-2-carboxylic acid ethyl ester  (4) Preparation

2,4-dihydroxybenzoate (182 mg, 1 mmol) having an ester group as the above [Formula II] compound was used as an aldehyde (S)-(-)-citronellal (308 mg). , 2 mmol) and EDDA (36 mg, 0.2 mmol) / TEA (2 mL) as a catalyst were reacted under reflux conditions for 12 hours using a compound catalyst as shown in [Table 6]. Compound 4 (267 mg, 84%).

Formula II Compound Aldehyde Reaction time product yield

(S)-(-)-citronellal 12

84

Spectroscopic data for the compound 4 is as follows.

Compound 4:

[α] _D ²⁰ +142.3 ^o (c 0.30, CHCl ₃ );

¹ H NMR (CDCl ₃ , 300 MHz) δ 11.7 (1H, s), 7.58 (1H, d, J = 8.8 Hz), 6.28 (1H, d, J = 8.8 Hz), 4.32 (2H, q, J = 7.1 Hz), 3.18 (1H, broad, J = 12.6 Hz), 2.52-2.43 (1H, m), 1.83-1.79 (2H, m), 1.64-1.53 (3H, m), 1.42-1.33 (1H, m), 1.37 (3H, s), 1.35 (3H, t, J = 7.1 Hz), 1.14-1.04 (1H, m), 1.05 (3H, s), 0.91 (3H, d, J = 6.6 Hz);

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.8, 162.6, 160.1, 128.6, 112.9, 109.4, 104.4, 78.3, 60.8, 48.7, 38.3, 35.4, 35.2, 27.9, 27.5, 22.5, 19.0, 17.6, 14.2;

IR (neat) 2924, 2868, 1659, 1620, 1582, 1373, 1331, 1258, 1208, 1138, 1020, 797 cm ^-1 .

Example  5.

(-)-One- Hydroxy -3,6,6,9- tetramethyl -6a, 7,8,9,10,10a- hexahydro -6H-benzo [c] chromene-2-carboxylic acid ethyl ester  (5a) and (-)-1- Hydroxy -3,6,6,9- tetramethyl -6a, 7,8,9,10,10a- hexahydro -6H- benzo [c] chromene-2-carboxylic acid  ethyl ester  (5b) Preparation

2,4-Dihydroxy-6-methylbenzoate (196 mg, 1.0 mmol) having an ester group as the above [Formula II] compound was used as an aldehyde (R)-(+)-citronellal (308 mg, 2.0 mmol). ) Or (S)-(-)-citronellal (308 mg, 2.0 mmol) and reacted under reflux conditions for 12 hours using an EDDA (36 mg, 0.2 mmol) / TEA (2 mL) mixed catalyst as a catalyst. Compounds 5a (289 mg, 87%) and 5b (286 mg, 86%) were obtained as shown in the following [Table 7].

Formula II Compound Aldehyde Reaction time product yield

   (R)-(+)-citronellal    12

   87

   (S)-(-)-citronellal    12

   86

Spectroscopic data for products 5a and 5b are as follows.

Compound 5a:

[α] _D ²⁰ -130.6 ^o (c 0.30, CHCl ₃ );

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.3 (1H, s), 6.16 (1H, s), 4.35 (2H, q, J = 7.1 Hz), 3.17 (1H, br d, J = 12.6 Hz), 2.52-2.43 (1H, m), 2.43 (3H, s), 1.85-1.79 (2H, m), 1.67-1.59 (3H, m), 1.44-1.35 (1H, m), 1.37 (3H, t, J = 7.1 Hz), 1.35 (3H, s), 1.14-1.04 (1H, m), 1.04 (3H, s), 0.92 (3H, d, J = 6.6 Hz);

¹³ C NMR (CDCl ₃ , 75 MHz) δ 172.5, 164.2, 158.5, 140.3, 112.6, 110.9, 104.3, 78.2, 61.0, 49.0, 38.4, 35.5, 35.2, 32.7, 28.0, 27.5, 24.2, 22.5, 19.1, 14.3 ;

IR (neat) 2926, 1644, 1568, 1454, 1402, 1368, 1316, 1267, 1198, 1142, 1022, 928, 812 cm ^-1 .

Compound 5b:

[α] _D ²⁰ +135.5 ^o (c 0.30, CHCl ₃ );

Example  6.

(-)-6,6,9- Trimethyl -6a, 7,8,9,10,10a- hexahydro -6H-dibenzo [c, h] chromene (6a) and (-)-6,6,9-Trimethyl-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [c, h] chromene  (6b)

Produce

1-naphthol (144 mg, 1.0 mmol) having two benzene rings as the [Formula II] compound was used as an aldehyde (R)-(+)-citronellal (308 mg, 2.0 mmol) or (S )-(-)-citronellal (308 mg, 2.0 mmol) was used, and the reaction was carried out under reflux condition of xylene for 8 hours using EDDA (36 mg, 0.2 mmol) / TEA (2 mL) mixed catalyst as a catalyst. 8] were obtained Compound 6a (191 mg, 68%) and 6b (196 mg, 70%), respectively.

Formula II Compound Aldehyde Reaction time product yield

   (R)-(+)-citronellal    8

   68

   (S)-(-)-citronellal    8

   70

Spectroscopic data for products 6a and 6b are as follows.

Compound 6a:

[α] _D ²⁰ -57.9 ^o (c 1.02, CHCl ₃ );

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.36-8.32 (1H, m), 7.82-7.79 (1H, m), 7.51-7.46 (2H, m), 7.43-7.39 (2H, m), 2.66-2.54 (2H, m), 1.94-1.90 (2H, m), 1.78-1.66 (1H, m), 1.61 (3H, s), 1.58-1.49 (1H, m), 1.29-1.11 (2H, m), 1.08 (3H, doublet, J = 6.6 Hz) 1.00-0.96 (1H, m);

¹³ C NMR (CDCl ₃ , 75 MHz) δ 147.8, 133.0, 127.2, 125.5, 124.8, 124.1, 122.0, 121.9, 118.7, 118.4, 77.6, 47.1, 39.7, 35.9, 34.8, 32.6, 28.0, 27.6, 22.6, 20.1 ;

IR (neat) 3055, 2922, 1572, 1507, 1458, 1385, 1265, 1209, 1144, 1096, 1020, 939, 909, 847, 745 cm ^-1 .

Compound 6b:

[α] _D ²⁰ +60.5 ^o (c 1.10, CHCl ₃ );

Example  7.

(-)-2,5,5- Trimethyl -1,3,4,4a, 5,12c hexahydro -2H-6-oxabenzo [c] phenanthrene (7a) and (-)-2,5,5- Trimethyl Preparation of -1,3,4,4a, 5,12c-hexahydro-2H-6-oxabenzo [c] phenanthrene (7b)

2-naphthol (144 mg, 1.0 mmol) having two benzene rings as the general formula II compound was selected from (R)-(+)-citronellal (308 mg, 2.0 mmol) or (S)-as an aldehyde. (-)-citronellal (308 mg, 2.0 mmol) was used, and the reaction was carried out under reflux conditions of xylene for 12 hours using an EDDA (36 mg, 0.2 mmol) / TEA (2 mL) mixed catalyst as a catalyst. Compounds 7a (202 mg, 72%) and 7b (210 mg, 75%) were obtained as in, respectively.

Formula II Compound Aldehyde Reaction time product yield

    (R)-(+)-citronellal     12

    72

    (S)-(-)-citronellal     12

    75

Spectroscopic data for the products 7a, 7b are as follows.

Compound 7a:

[α] _D ²⁰ -55.6 ^o (c 0.50, CHCl ₃ );

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.93 (1H, d, J = 8.4 Hz), 7.83 (1H, d, J = 8.0 Hz), 7.67 (1H, d, J = 8.9 Hz), 7.53 (1H) , dt, J = 8.4, 1.4 Hz), 7.38 (1H, dt, J = 8.0, 1.1 Hz), 7.14 (1H, d, J = 8.9 Hz), 2.95-2.80 (1H, m), 2.07-1.95 ( 2H, m), 1.75-1.67 (1H, m), 1.55 (3H, s), 1.44-1.20 (3H, m), 1.16 (3H, s), 1.05 (3H, d, J = 6.5 Hz), 1.00 -0.88 (1 H, m);

¹³ C NMR (CDCl ₃ , 75 MHz) δ 151.5, 132.4, 129.7, 128.8, 128.0, 125.2, 124.2, 122.6, 120.0, 117.4, 77.6, 51.2, 42.5, 36.7, 36.0, 33.3, 28.4, 27.6, 22.6, 18.4 ;

IR (neat) 3059, 2926, 1620, 1599, 1512, 1460, 1386, 1240, 1213, 1144, 1001, 981, 956, 908, 814, 748 cm ^-1 .

Compound 7b:

[a] _D ^{2 0} +56.1 ^o (c 0.40, CHCl ₃ );

Claims (6)

A method for producing a hexahydrocannabiol derivative of [Formula II] by reacting a compound of Formula [I] with an aldehyde having an unsaturated bond in a non-reactive organic solvent in the presence of a catalyst. [Formula I]

In Formula [I], R ₁ is hydrogen, OH, OCH ₃ , OEt, ether group, algenyl group, R ₂ is hydrogen, carbonyl, ester group, and alkenyl group, R ₃ is hydrogen, methyl, Alkyl groups and alkyl groups such as ethyl, pentanyl and R ₄ means hydrogen, alkyl and alkenyl groups Or A in the general formula [I] means naphthyl, quinolyl, isoquinolyl, quinolizylyl, quinolsalinyl and dibenzofuryl ring. [Formula II]

In Formula [II], R ₅ is a hydrocarbon having a hydrogen, a hydroxy group, a carbonyl group, or an ester group, or in [Formula II], R ₅ is a naphthyl, quinolyl, isoquinolyl, quinoli with a B ring. A group selected from genyl, quinolsalinyl and dibenzofuryl. The method of claim 1, Aldehydes having unsaturated bonds have 8 to 18 carbon atoms, unsaturated aldehydes having double bonds between carbons, citral, citronellal, citronellyl oxyacetalde hyde), a method for producing hexahydrocannabiol derivatives, which is any one selected from cyclamen aldehyde, hydroxycitronellal, lilial and bourgeonal. The method of claim 2 The aldehyde having an unsaturated bond is (R)-(+)-citronellal or (S)-(-)-cytronellal. The method of claim 1, The non-reactive organic solvent is dichloromethane, chloroform, 1-2-dibromoethane, 1-bromo-2-chloroethane, 1,1-dibromoethane, 2-chloro furophane, 1-dodofuropan Halogenated hydrocarbons such as chlorobenzene, bromobenzene and 1,2-dichlorobenzene: aromatic solvents such as benzene, toluene, xylenes: selected from ethers such as diethyl ether, dimethyl ether, dimethyl ether and diisopurofyl ether How to prepare a hexahydrocannabiol derivative. The method of claim 1, Wherein the non-reactive organic solvent is xylene. The method of claim 1 Wherein the catalyst is a method for producing a hexahydrocannabiol derivatives using a catalyst obtained by mixing 20 mol% and 2 mL of ethylenediamine diacetate and triethylamine, respectively.